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Vol. 15, Issue 5, 2025
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ISSN2095-1779
CN61-1484/R
Editor-in-Chief: Langchong He
Impact Factor 2024: 8.9
CiteScore 2024: 11.1
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2025, 15(5): 101344.
doi: 10.1016/j.jpha.2025.101344
Abstract:
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2025, 15(5): 101131.
doi: 10.1016/j.jpha.2024.101131
Abstract:
A traditional Chinese medicine (TCM) monomer is a bioactive compound extracted from Chinese herbal medicines possessing determined biological activity and pharmacological effects, and has gained much attention for treating neuronal diseases. However, the application of TCM monomers is limited by their low solubility and poor ability to cross the blood-brain barrier (BBB). Exosomes are small extracellular vesicles (EVs) ranging in size from 30 to 150 nm in diameter and can be used as drug delivery carriers that directly target cells or tissues with unique advantages, including low toxicity, low immunogenicity, high stability in blood, and the ability to cross the BBB. This review discusses the biogenesis, components, stability, surface modification, isolation technology, advantages, and disadvantages of exosomes as drug carriers and compares exosomes and other similar drug delivery systems. Furthermore, exosome-encapsulated TCM monomers exert neuroprotective roles, such as anti-inflammation, anti-apoptosis, anti-mitophagy, and anti-oxidation, in various neuronal diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), and cerebral ischemia and reperfusion (CI/R) injury, as well as anti-drug resistance, anti-tumorigenesis, anti-angiogenesis, and promotion of apoptosis in brain tumors, providing more inspiration to promote the development of an exosome-based delivery tool in targeted therapy for neuronal diseases.
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2025, 15(5): 101156.
doi: 10.1016/j.jpha.2024.101156
Abstract:
The microstructures of pharmaceutical preparations play a pivotal role in determining their critical quality attributes (CQAs), such as drug release, content uniformity, and stability, which greatly impact the safety and efficacy of drugs. Unlike the inherent molecular structures of active pharmaceutical ingredients (APIs) and excipients, the microstructures of pharmaceutical preparations are developed during the formulation process, presenting unique analytical challenges. In this review, we primarily focus on presenting the research methods used to elucidate the microstructures of pharmaceutical preparations, including X-ray imaging (XRI), scanning electron microscopy (SEM), atomic force microscopy (AFM), Raman spectroscopy, infrared (IR) spectroscopy, and rheometer technology. Subsequently, we highlight the applications, advantages, and limitations of these methods. Finally, we discuss the current challenges and future perspectives in this field. This review aims to provide a comprehensive reference for understanding the microstructures of pharmaceutical preparations, offering new insights and potential advancements in their development.
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2025, 15(5): 101130.
doi: 10.1016/j.jpha.2024.101130
Abstract:
Diabetes, a metabolic disease stemming from impaired or defective insulin secretion, ranks among the most severe chronic illnesses globally. While several approved drugs exist for its treatment, they often come with multiple side effects. Therefore, there is a pressing need for safe and effective anti-diabetic medications. Traditional Chinese medicine has recognized Lycium barbarum (LB; goji berry) plant, commonly known as “wolfberry fruit” in China, for over 2,000 years. Natural compounds derived from LB show promise in reducing diabetes levels. Although research on the impact of LB on diabetes is still limited, our review aims to explore the potential of LB in reducing the risk of diabetes and examine the underlying mechanisms involved. LB can modulate diabetes through various pathways, such as inhibiting α-amylase and α-glucosidase activities, promoting β-cell proliferation, stimulating insulin secretion, inhibiting glucagon secretion, improving insulin resistance and glucose tolerance, and enhancing antioxidant and anti-inflammatory activities. Additionally, LB improves gut flora and immunomodulation, further aiding diabetes management. These findings highlight the potential clinical utility of LB in managing diabetes and its complications within the framework of evidence-based modern medicine.
2022, 12(3): 355-364.
doi: 10.1016/j.jpha.2021.08.002
摘要：
Antibiotics are a category of chemical compounds used to treat bacterial infections and are widely applied in cultivation, animal husbandry, aquaculture, and pharmacy. Currently, residual antibiotics and their metabolites pose a potential risk of allergic reactions, bacterial resistance, and increased cancer incidence. Residual antibiotics and the resulting bacterial antibiotic resistance have been recognized as a global challenge that has attracted increasing attention. Therefore, monitoring antibiotics is a critical way to limit the ecological risks from antibiotic pollution. Accordingly, it is desirable to devise new analytical platforms to achieve efficient antibiotic detection with excellent sensitivity and specificity. Quantum dots (QDs) are regarded as an ideal material for use in the development of antibiotic detection biosensors. In this review, we characterize different types of QDs, such as silicon, chalcogenide, carbon, and other doped QDs, and summarize the trends in QD-based antibiotic detection. QD-based sensing applications are classified according to their recognition strategies, including molecularly imprinted polymers (MIPs), aptamers, and immunosensors. We discuss the advantages of QD-derived antibiotic sensors, including low cost, good sensitivity, excellent stability, and fast response, and illustrate the current challenges in this field.
Antibiotics are a category of chemical compounds used to treat bacterial infections and are widely applied in cultivation, animal husbandry, aquaculture, and pharmacy. Currently, residual antibiotics and their metabolites pose a potential risk of allergic reactions, bacterial resistance, and increased cancer incidence. Residual antibiotics and the resulting bacterial antibiotic resistance have been recognized as a global challenge that has attracted increasing attention. Therefore, monitoring antibiotics is a critical way to limit the ecological risks from antibiotic pollution. Accordingly, it is desirable to devise new analytical platforms to achieve efficient antibiotic detection with excellent sensitivity and specificity. Quantum dots (QDs) are regarded as an ideal material for use in the development of antibiotic detection biosensors. In this review, we characterize different types of QDs, such as silicon, chalcogenide, carbon, and other doped QDs, and summarize the trends in QD-based antibiotic detection. QD-based sensing applications are classified according to their recognition strategies, including molecularly imprinted polymers (MIPs), aptamers, and immunosensors. We discuss the advantages of QD-derived antibiotic sensors, including low cost, good sensitivity, excellent stability, and fast response, and illustrate the current challenges in this field.
2023, 13(3): 239-254.
doi: 10.1016/j.jpha.2022.12.001
摘要：
Flavonoids such as baohuoside I and icaritin are the major active compounds in Epimedii Folium (EF) and possess excellent therapeutic effects on various diseases. Encouragingly, in 2022, icaritin soft capsules were approved to reach the market for the treatment of hepatocellular carcinoma (HCC) by National Medical Products Administration (NMPA) of China. Moreover, recent studies demonstrate that icaritin can serve as immune-modulating agent to exert anti-tumor effects. Nonetheless, both production efficiency and clinical applications of epimedium flavonoids have been restrained because of their low content, poor bioavailability, and unfavorable in vivo delivery efficiency. Recently, various strategies, including enzyme engineering and nanotechnology, have been developed to increase productivity and activity, improve delivery efficiency, and enhance therapeutic effects of epimedium flavonoids. In this review, the structure-activity relationship of epimedium flavonoids is described. Then, enzymatic engineering strategies for increasing the productivity of highly active baohuoside I and icaritin are discussed. The nanomedicines for overcoming in vivo delivery barriers and improving therapeutic effects of various diseases are summarized. Finally, the challenges and an outlook on clinical translation of epimedium flavonoids are proposed.
Flavonoids such as baohuoside I and icaritin are the major active compounds in Epimedii Folium (EF) and possess excellent therapeutic effects on various diseases. Encouragingly, in 2022, icaritin soft capsules were approved to reach the market for the treatment of hepatocellular carcinoma (HCC) by National Medical Products Administration (NMPA) of China. Moreover, recent studies demonstrate that icaritin can serve as immune-modulating agent to exert anti-tumor effects. Nonetheless, both production efficiency and clinical applications of epimedium flavonoids have been restrained because of their low content, poor bioavailability, and unfavorable in vivo delivery efficiency. Recently, various strategies, including enzyme engineering and nanotechnology, have been developed to increase productivity and activity, improve delivery efficiency, and enhance therapeutic effects of epimedium flavonoids. In this review, the structure-activity relationship of epimedium flavonoids is described. Then, enzymatic engineering strategies for increasing the productivity of highly active baohuoside I and icaritin are discussed. The nanomedicines for overcoming in vivo delivery barriers and improving therapeutic effects of various diseases are summarized. Finally, the challenges and an outlook on clinical translation of epimedium flavonoids are proposed.
2022, 12(4): 541-555.
doi: 10.1016/j.jpha.2021.10.003
摘要：
Berberine (BBR), an isoquinoline alkaloid, has been found in many plants, such as Coptis chinensis Franch and Phellodendron chinense Schneid. Although BBR has a wide spectrum of pharmacological effects, its oral bioavailability is extremely low. In recent years, gut microbiota has emerged as a cynosure to understand the mechanisms of action of herbal compounds. Numerous studies have demonstrated that due to its low bioavailability, BBR can interact with the gut microbiota, thereby exhibiting altered pharmacological effects. However, no systematic and comprehensive review has summarized these interactions and their corresponding influences on pharmacological effects. Here, we describe the direct interactive relationships between BBR and gut microbiota, including regulation of gut microbiota composition and metabolism by BBR and metabolization of BBR by gut microbiota. In addition, the complex interactions between gut microbiota and BBR as well as the side effects and personalized use of BBR are discussed. Furthermore, we provide our viewpoint on future research directions regarding BBR and gut microbiota. This review not only helps to explain the mechanisms underlying BBR activity but also provides support for the rational use of BBR in clinical practice.
Berberine (BBR), an isoquinoline alkaloid, has been found in many plants, such as Coptis chinensis Franch and Phellodendron chinense Schneid. Although BBR has a wide spectrum of pharmacological effects, its oral bioavailability is extremely low. In recent years, gut microbiota has emerged as a cynosure to understand the mechanisms of action of herbal compounds. Numerous studies have demonstrated that due to its low bioavailability, BBR can interact with the gut microbiota, thereby exhibiting altered pharmacological effects. However, no systematic and comprehensive review has summarized these interactions and their corresponding influences on pharmacological effects. Here, we describe the direct interactive relationships between BBR and gut microbiota, including regulation of gut microbiota composition and metabolism by BBR and metabolization of BBR by gut microbiota. In addition, the complex interactions between gut microbiota and BBR as well as the side effects and personalized use of BBR are discussed. Furthermore, we provide our viewpoint on future research directions regarding BBR and gut microbiota. This review not only helps to explain the mechanisms underlying BBR activity but also provides support for the rational use of BBR in clinical practice.
2022, 12(3): 394-405.
doi: 10.1016/j.jpha.2021.07.002
摘要：
Nuclear factor κB (NF-κB) is a ubiquitous regulator of the signalome and is indispensable for various biological cell functions. NF-κB consists of five transcription factors that execute both cytoplasmic and nuclear signaling processes in cells. NF-κB is the only signaling molecule that governs both pro- and anti-apoptotic, and pro- and anti-inflammatory responses. This is due to the canonical and non-canonical components of the NF-κB signaling pathway. Together, these pathways orchestrate cancer-related inflammation, hyperplasia, neoplasia, and metastasis. Non-canonical NF-κB pathways are particularly involved in the chemoresistance of cancer cells. In view of its pivotal role in cancer progression, NF-κB represents a potentially significant therapeutic target for modifying tumor cell behavior. Several phytochemicals are known to modulate NF-κB pathways through the stabilization of its inhibitor, IκB, by inhibiting phosphorylation and ubiquitination thereof. Several natural pharmacophores are known to inhibit the nuclear translocation of NF-κB and associated pro-inflammatory responses and cell survival pathways. In view of this and the high degree of specificity exhibited by various phytochemicals for the NF-κB component, we herein present an in-depth overview of these phytochemicals and discuss their mode of interaction with the NF-κB signaling pathways for controlling the fate of tumor cells for cancer-directed interventions.
Nuclear factor κB (NF-κB) is a ubiquitous regulator of the signalome and is indispensable for various biological cell functions. NF-κB consists of five transcription factors that execute both cytoplasmic and nuclear signaling processes in cells. NF-κB is the only signaling molecule that governs both pro- and anti-apoptotic, and pro- and anti-inflammatory responses. This is due to the canonical and non-canonical components of the NF-κB signaling pathway. Together, these pathways orchestrate cancer-related inflammation, hyperplasia, neoplasia, and metastasis. Non-canonical NF-κB pathways are particularly involved in the chemoresistance of cancer cells. In view of its pivotal role in cancer progression, NF-κB represents a potentially significant therapeutic target for modifying tumor cell behavior. Several phytochemicals are known to modulate NF-κB pathways through the stabilization of its inhibitor, IκB, by inhibiting phosphorylation and ubiquitination thereof. Several natural pharmacophores are known to inhibit the nuclear translocation of NF-κB and associated pro-inflammatory responses and cell survival pathways. In view of this and the high degree of specificity exhibited by various phytochemicals for the NF-κB component, we herein present an in-depth overview of these phytochemicals and discuss their mode of interaction with the NF-κB signaling pathways for controlling the fate of tumor cells for cancer-directed interventions.
2022, 12(3): 406-414.
doi: 10.1016/j.jpha.2021.12.005
摘要：
The cyanobacterium Arthrospira platensis, spirulina, is a source of pigments such as phycobiliprotein and phycocyanin. Phycocyanin is used in the food, cosmetics, and pharmaceutical industries because of its antioxidant, anti-inflammatory, and anticancer properties. The different steps involved in extraction and purification of this protein can alter the final properties. In this review, the stability of phycocyanin (pH, temperature, and light) is discussed, considering the physicochemical parameters of kinetic modeling. The optimal working pH range for phycocyanin is between 5.5 and 6.0 and it remains stable up to 45 ℃; however, exposure to relatively high temperatures or acidic pH decreases its half-life and increases the degradation kinetic constant. Phycobiliproteins are sensitive to light; preservatives such as mono- and di-saccharides, citric acid, or sodium chloride appear to be effective stabilizing agents. Encapsulation within nano- or micro-structured materials such as nanofibers, microparticles, or nanoparticles, can also preserve or enhance its stability.
The cyanobacterium Arthrospira platensis, spirulina, is a source of pigments such as phycobiliprotein and phycocyanin. Phycocyanin is used in the food, cosmetics, and pharmaceutical industries because of its antioxidant, anti-inflammatory, and anticancer properties. The different steps involved in extraction and purification of this protein can alter the final properties. In this review, the stability of phycocyanin (pH, temperature, and light) is discussed, considering the physicochemical parameters of kinetic modeling. The optimal working pH range for phycocyanin is between 5.5 and 6.0 and it remains stable up to 45 ℃; however, exposure to relatively high temperatures or acidic pH decreases its half-life and increases the degradation kinetic constant. Phycobiliproteins are sensitive to light; preservatives such as mono- and di-saccharides, citric acid, or sodium chloride appear to be effective stabilizing agents. Encapsulation within nano- or micro-structured materials such as nanofibers, microparticles, or nanoparticles, can also preserve or enhance its stability.
2023, 13(6): 673-682.
doi: 10.1016/j.jpha.2023.04.015
摘要：
Glucose transporter 1 (GLUT1) overexpression in tumor cells is a potential target for drug therapy, but few studies have reported screening GLUT1 inhibitors from natural or synthetic compounds. With current analysis techniques, it is difficult to accurately monitor the GLUT1 inhibitory effect of drug molecules in real-time. We developed a cell membrane-based glucose sensor (CMGS) that integrated a hydrogel electrode with tumor cell membranes to monitor GLUT1 transmembrane transport and screen for GLUT1 inhibitors in traditional Chinese medicines (TCMs). CMGS is compatible with cell membranes of various origins, including different types of tumors and cell lines with GLUT1 expression knocked down by small interfering RNA or small molecules. Based on CMGS continuous monitoring technique, we investigated the glucose transport kinetics of cell membranes with varying levels of GLUT1 expression. We used CMGS to determine the GLUT1-inhibitory effects of drug monomers with similar structures from Scutellaria baicalensis and catechins families. Results were consistent with those of the cellular glucose uptake test and molecular-docking simulation. CMGS could accurately screen drug molecules in TCMs that inhibit GLUT1, providing a new strategy for studying transmembrane protein-receptor interactions.
Glucose transporter 1 (GLUT1) overexpression in tumor cells is a potential target for drug therapy, but few studies have reported screening GLUT1 inhibitors from natural or synthetic compounds. With current analysis techniques, it is difficult to accurately monitor the GLUT1 inhibitory effect of drug molecules in real-time. We developed a cell membrane-based glucose sensor (CMGS) that integrated a hydrogel electrode with tumor cell membranes to monitor GLUT1 transmembrane transport and screen for GLUT1 inhibitors in traditional Chinese medicines (TCMs). CMGS is compatible with cell membranes of various origins, including different types of tumors and cell lines with GLUT1 expression knocked down by small interfering RNA or small molecules. Based on CMGS continuous monitoring technique, we investigated the glucose transport kinetics of cell membranes with varying levels of GLUT1 expression. We used CMGS to determine the GLUT1-inhibitory effects of drug monomers with similar structures from Scutellaria baicalensis and catechins families. Results were consistent with those of the cellular glucose uptake test and molecular-docking simulation. CMGS could accurately screen drug molecules in TCMs that inhibit GLUT1, providing a new strategy for studying transmembrane protein-receptor interactions.
2023, 13(4): 355-366.
doi: 10.1016/j.jpha.2022.12.003
摘要：
Neutrophil elastase (NE), a major protease in the primary granules of neutrophils, is involved in microbicidal activity. NE is an important factor promoting inflammation, has bactericidal effects, and shortens the inflammatory process. NE also regulates tumor growth by promoting metastasis and tumor microenvironment remodeling. However, NE plays a role in killing tumors under certain conditions and promotes other diseases such as pulmonary ventilation dysfunction. Additionally, it plays a complex role in various physiological processes and mediates several diseases. Sivelestat, a specific NE inhibitor, has strong potential for clinical application, particularly in the treatment of coronavirus disease 2019 (COVID-19). This review discusses the pathophysiological processes associated with NE and the potential clinical applications of sivelestat.
Neutrophil elastase (NE), a major protease in the primary granules of neutrophils, is involved in microbicidal activity. NE is an important factor promoting inflammation, has bactericidal effects, and shortens the inflammatory process. NE also regulates tumor growth by promoting metastasis and tumor microenvironment remodeling. However, NE plays a role in killing tumors under certain conditions and promotes other diseases such as pulmonary ventilation dysfunction. Additionally, it plays a complex role in various physiological processes and mediates several diseases. Sivelestat, a specific NE inhibitor, has strong potential for clinical application, particularly in the treatment of coronavirus disease 2019 (COVID-19). This review discusses the pathophysiological processes associated with NE and the potential clinical applications of sivelestat.
2022, 12(1): 104-112.
doi: 10.1016/j.jpha.2021.04.004
摘要：
Chromium is a harmful contaminant showing mutagenicity and carcinogenicity. Therefore, detection of chromium requires the development of low-cost and high-sensitivity sensors. Herein, blue-fluorescent carbon quantum dots were synthesized by one-step hydrothermal method from alkali-soluble Poria cocos polysaccharide, which is green source, cheap and easy to obtain, and has no pharmacological activity due to low water solubility. These carbon quantum dots exhibit good fluorescence stability, water solubility, anti-interference and low cytotoxicity, and can be specifically combined with the detection of Cr(VI) to form a non-fluorescent complex that causes fluorescence quenching, so they can be used as a label-free nanosensor. High-sensitivity detection of Cr(VI) was achieved through internal filtering and static quenching effects. The fluorescence quenching degree of carbon dots fluorescent probe showed a good linear relationship with Cr(VI) concentration in the range of 1–100 μM. The linear equation was F0/F = 0.9942 + 0.01472 [Cr(VI)] (R2 = 0.9922), and the detection limit can be as low as 0.25 μM (S/N = 3), which has been successfully applied to Cr(VI) detection in actual water samples herein.
Chromium is a harmful contaminant showing mutagenicity and carcinogenicity. Therefore, detection of chromium requires the development of low-cost and high-sensitivity sensors. Herein, blue-fluorescent carbon quantum dots were synthesized by one-step hydrothermal method from alkali-soluble Poria cocos polysaccharide, which is green source, cheap and easy to obtain, and has no pharmacological activity due to low water solubility. These carbon quantum dots exhibit good fluorescence stability, water solubility, anti-interference and low cytotoxicity, and can be specifically combined with the detection of Cr(VI) to form a non-fluorescent complex that causes fluorescence quenching, so they can be used as a label-free nanosensor. High-sensitivity detection of Cr(VI) was achieved through internal filtering and static quenching effects. The fluorescence quenching degree of carbon dots fluorescent probe showed a good linear relationship with Cr(VI) concentration in the range of 1–100 μM. The linear equation was F0/F = 0.9942 + 0.01472 [Cr(VI)] (R2 = 0.9922), and the detection limit can be as low as 0.25 μM (S/N = 3), which has been successfully applied to Cr(VI) detection in actual water samples herein.
2022, 12(4): 517-529.
doi: 10.1016/j.jpha.2022.03.001
摘要：
Sample preparation is considered as the bottleneck step in bioanalysis because each biological matrix has its own unique challenges and complexity. Competent sample preparation to extract the desired analytes and remove redundant components is a crucial step in each bioanalytical approach. The matrix effect is a key hurdle in bioanalytical sample preparation, which has gained extensive consideration. Novel sample preparation techniques have advantages over classical techniques in terms of accuracy, automation, ease of sample preparation, storage, and shipment and have become increasingly popular over the past decade. Our objective is to provide a broad outline of current developments in various bioanalytical sample preparation techniques in chromatographic and spectroscopic examinations. In addition, how these techniques have gained considerable attention over the past decade in bioanalytical research is mentioned with preferred examples. Modern trends in bioanalytical sample preparation techniques, including sorbent-based microextraction techniques, are primarily emphasized.
Sample preparation is considered as the bottleneck step in bioanalysis because each biological matrix has its own unique challenges and complexity. Competent sample preparation to extract the desired analytes and remove redundant components is a crucial step in each bioanalytical approach. The matrix effect is a key hurdle in bioanalytical sample preparation, which has gained extensive consideration. Novel sample preparation techniques have advantages over classical techniques in terms of accuracy, automation, ease of sample preparation, storage, and shipment and have become increasingly popular over the past decade. Our objective is to provide a broad outline of current developments in various bioanalytical sample preparation techniques in chromatographic and spectroscopic examinations. In addition, how these techniques have gained considerable attention over the past decade in bioanalytical research is mentioned with preferred examples. Modern trends in bioanalytical sample preparation techniques, including sorbent-based microextraction techniques, are primarily emphasized.
2022, 12(1): 35-57.
doi: 10.1016/j.jpha.2021.07.004
摘要：
Moroccan medicinal plants exhibit several pharmacological properties such as antimicrobial, anticancer, antidiabetic, analgesic, and anti-inflammatory effects, which are related to the presence of numerous bioactive compounds, including phenolic acids, flavonoids, and terpenoids. In the present review, we systematically evaluate previously published reports on the anti-inflammatory and analgesic effects of Moroccan medicinal plants. The in vitro investigations revealed that Moroccan medicinal plants inhibit several enzymes related to inflammatory processes, whereas in vivo studies noted significant anti-inflammatory and analgesic effects as demonstrated using different experimental models. Various bioactive compounds exhibiting in vitro and in vivo anti-inflammatory and analgesic effects, with diverse mechanisms of action, have been identified. Some plants and their bioactive compounds reveal specific secondary metabolites that possess important anti-inflammatory effects in clinical investigations. Our review proposes the potential applications of Moroccan medicinal plants as sources of anti-inflammatory and analgesic agents.
Moroccan medicinal plants exhibit several pharmacological properties such as antimicrobial, anticancer, antidiabetic, analgesic, and anti-inflammatory effects, which are related to the presence of numerous bioactive compounds, including phenolic acids, flavonoids, and terpenoids. In the present review, we systematically evaluate previously published reports on the anti-inflammatory and analgesic effects of Moroccan medicinal plants. The in vitro investigations revealed that Moroccan medicinal plants inhibit several enzymes related to inflammatory processes, whereas in vivo studies noted significant anti-inflammatory and analgesic effects as demonstrated using different experimental models. Various bioactive compounds exhibiting in vitro and in vivo anti-inflammatory and analgesic effects, with diverse mechanisms of action, have been identified. Some plants and their bioactive compounds reveal specific secondary metabolites that possess important anti-inflammatory effects in clinical investigations. Our review proposes the potential applications of Moroccan medicinal plants as sources of anti-inflammatory and analgesic agents.
2022, 12(1): 1-14.
doi: 10.1016/j.jpha.2021.03.009
摘要：
Interference with quorum sensing (QS) represents an antivirulence strategy with a significant promise for the treatment of bacterial infections and a new approach to restoring antibiotic tolerance. Over the past two decades, a novel series of studies have reported that quorum quenching approaches and the discovery of quorum sensing inhibitors (QSIs) have a strong impact on the discovery of anti-infective drugs against various types of bacteria. The discovery of QSI was demonstrated to be an appropriate strategy to expand the anti-infective therapeutic approaches to complement classical antibiotics and antimicrobial agents. For the discovery of QSIs, diverse approaches exist and develop in-step with the scale of screening as well as specific QS systems. This review highlights the latest findings in strategies and methodologies for QSI screening, involving activity-based screening with bioassays, chemical methods to seek bacterial QS pathways for QSI discovery, virtual screening for QSI screening, and other potential tools for interpreting QS signaling, which are innovative routes for future efforts to discover additional QSIs to combat bacterial infections.
Interference with quorum sensing (QS) represents an antivirulence strategy with a significant promise for the treatment of bacterial infections and a new approach to restoring antibiotic tolerance. Over the past two decades, a novel series of studies have reported that quorum quenching approaches and the discovery of quorum sensing inhibitors (QSIs) have a strong impact on the discovery of anti-infective drugs against various types of bacteria. The discovery of QSI was demonstrated to be an appropriate strategy to expand the anti-infective therapeutic approaches to complement classical antibiotics and antimicrobial agents. For the discovery of QSIs, diverse approaches exist and develop in-step with the scale of screening as well as specific QS systems. This review highlights the latest findings in strategies and methodologies for QSI screening, involving activity-based screening with bioassays, chemical methods to seek bacterial QS pathways for QSI discovery, virtual screening for QSI screening, and other potential tools for interpreting QS signaling, which are innovative routes for future efforts to discover additional QSIs to combat bacterial infections.
2023, 13(9): 960-967.
doi: 10.1016/j.jpha.2023.06.001
摘要：
Use of gold nanoparticles (GNPs) in medicine is an emerging field of translational research with vast clinical implications and exciting therapeutic potential. However, the safety of using GNPs in human subjects is an important question that remains unanswered. This study reviews over 20 clinical trials focused on GNP safety and aims to summarize all the clinical studies, completed and ongoing, to identify whether GNPs are safe to use in humans as a therapeutic platform. In these studies, GNPs were implemented as drug delivery devices, for photothermal therapy, and utilized for their intrinsic therapeutic effects by various routes of delivery. These studies revealed no major safety concerns with the use of GNPs; however, the number of trials and total patient number remains limited. Multi-dose, multi-center blinded trials are required to deepen our understanding of the use of GNPs in clinical settings to facilitate translation of this novel, multifaceted therapeutic device. Expanding clinical trials will require collaboration between clinicians, scientists, and biotechnology companies.
Use of gold nanoparticles (GNPs) in medicine is an emerging field of translational research with vast clinical implications and exciting therapeutic potential. However, the safety of using GNPs in human subjects is an important question that remains unanswered. This study reviews over 20 clinical trials focused on GNP safety and aims to summarize all the clinical studies, completed and ongoing, to identify whether GNPs are safe to use in humans as a therapeutic platform. In these studies, GNPs were implemented as drug delivery devices, for photothermal therapy, and utilized for their intrinsic therapeutic effects by various routes of delivery. These studies revealed no major safety concerns with the use of GNPs; however, the number of trials and total patient number remains limited. Multi-dose, multi-center blinded trials are required to deepen our understanding of the use of GNPs in clinical settings to facilitate translation of this novel, multifaceted therapeutic device. Expanding clinical trials will require collaboration between clinicians, scientists, and biotechnology companies.
2022, 12(5): 701-710.
doi: 10.1016/j.jpha.2022.05.001
摘要：
With the modernization and internationalization of traditional Chinese medicine (TCM), the requirement for quality control has increased. The quality marker (Q-marker) is an important standard in this field and has been implemented with remarkable success in recent years. However, the establishment of Q-markers remains fragmented and the process lacks systematicity, resulting in inconsistent quality control and insufficient correlation with clinical efficacy and safety of TCM. This review introduces four multimodal integrated approaches that contribute to the discovery of more comprehensive and accurate Q-markers, thus aiding in the establishment of new quality control patterns based on the characteristics and principles of TCM. These include the whole-process quality control strategy, chemical-activity-based screening method, efficacy, safety, and consistent combination strategy, and TCM theory-guided approach. Furthermore, methodologies and representative examples of these strategies are described, and important future directions and questions in this field are also proposed.
With the modernization and internationalization of traditional Chinese medicine (TCM), the requirement for quality control has increased. The quality marker (Q-marker) is an important standard in this field and has been implemented with remarkable success in recent years. However, the establishment of Q-markers remains fragmented and the process lacks systematicity, resulting in inconsistent quality control and insufficient correlation with clinical efficacy and safety of TCM. This review introduces four multimodal integrated approaches that contribute to the discovery of more comprehensive and accurate Q-markers, thus aiding in the establishment of new quality control patterns based on the characteristics and principles of TCM. These include the whole-process quality control strategy, chemical-activity-based screening method, efficacy, safety, and consistent combination strategy, and TCM theory-guided approach. Furthermore, methodologies and representative examples of these strategies are described, and important future directions and questions in this field are also proposed.
2022, 12(1): 29-34.
doi: 10.1016/j.jpha.2021.09.009
摘要：
The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has caused a devastating health crisis worldwide. In this review, we have discussed that prophylactic phytochemical quercetin supplementation in the form of foods or nutraceuticals may help manage the COVID-19 pandemic. The following evidence supports our argument. First, nuclear factor erythroid-derived 2-like 2 (NRF2) agonists abrogate replication of SARS-CoV-2 in lung cells, and quercetin is a potent NRF2 agonist. Second, quercetin exerts antiviral activity against several zoonotic coronaviruses, including SARS-CoV-2, mainly by inhibiting the entry of virions into host cells. Third, inflammatory pathways activated by nuclear factor kappa B, inflammasome, and interleukin-6 signals elicit cytokine release syndrome that promotes acute respiratory distress syndrome in patients with COVID-19, and quercetin inhibits these pro-inflammatory signals. Fourth, patients with COVID-19 develop thrombosis, and quercetin mitigates coagulation abnormalities by inhibiting plasma protein disulfide isomerase. This review provides a strong rationale for testing quercetin for the management of COVID-19.
The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has caused a devastating health crisis worldwide. In this review, we have discussed that prophylactic phytochemical quercetin supplementation in the form of foods or nutraceuticals may help manage the COVID-19 pandemic. The following evidence supports our argument. First, nuclear factor erythroid-derived 2-like 2 (NRF2) agonists abrogate replication of SARS-CoV-2 in lung cells, and quercetin is a potent NRF2 agonist. Second, quercetin exerts antiviral activity against several zoonotic coronaviruses, including SARS-CoV-2, mainly by inhibiting the entry of virions into host cells. Third, inflammatory pathways activated by nuclear factor kappa B, inflammasome, and interleukin-6 signals elicit cytokine release syndrome that promotes acute respiratory distress syndrome in patients with COVID-19, and quercetin inhibits these pro-inflammatory signals. Fourth, patients with COVID-19 develop thrombosis, and quercetin mitigates coagulation abnormalities by inhibiting plasma protein disulfide isomerase. This review provides a strong rationale for testing quercetin for the management of COVID-19.
2024, 14(11): 101013.
doi: 10.1016/j.jpha.2024.101013
摘要：
Green analytical chemistry (GAC) focuses on mitigating the adverse effects of analytical activities on human safety, human health, and environment. In addition to the 12 principles of GAC, proper GAC tools should be developed and employed to assess the greenness of different analytical assays. The 15 widely used GAC metrics, i.e., national environmental methods index (NEMI), advanced NEMI, assessment of green profile (AGP), chloroform-oriented toxicity estimation scale (ChlorTox Scale), Analytical Eco-Scale, Green Certificate Modified Eco-Scale, analytical method greenness score (AMGS), green analytical procedure index (GAPI), ComplexGAPI, red-green-blue (RGB) additive color model, RGB 12 algorithm, analytical greenness calculator (AGREE), AGREE preparation (AGREEprep), HEXAGON, and blue applicability grade index (BAGI), are selected as the typical tools. This article comprehensively presents and elucidates the principles, characteristics, merits, and demerits of 15 widely used GAC tools. This review is helpful for researchers to use the current GAC metrics to assess the environmental sustainability of analytical assays.
Green analytical chemistry (GAC) focuses on mitigating the adverse effects of analytical activities on human safety, human health, and environment. In addition to the 12 principles of GAC, proper GAC tools should be developed and employed to assess the greenness of different analytical assays. The 15 widely used GAC metrics, i.e., national environmental methods index (NEMI), advanced NEMI, assessment of green profile (AGP), chloroform-oriented toxicity estimation scale (ChlorTox Scale), Analytical Eco-Scale, Green Certificate Modified Eco-Scale, analytical method greenness score (AMGS), green analytical procedure index (GAPI), ComplexGAPI, red-green-blue (RGB) additive color model, RGB 12 algorithm, analytical greenness calculator (AGREE), AGREE preparation (AGREEprep), HEXAGON, and blue applicability grade index (BAGI), are selected as the typical tools. This article comprehensively presents and elucidates the principles, characteristics, merits, and demerits of 15 widely used GAC tools. This review is helpful for researchers to use the current GAC metrics to assess the environmental sustainability of analytical assays.
2022, 12(6): 824-838.
doi: 10.1016/j.jpha.2022.08.001
摘要：
Rabdosia serra (R. serra), an important component of Chinese herbal tea, has traditionally been used to treat hepatitis, jaundice, cholecystitis, and colitis. However, the chemical composition of R. serra and its effect against colitis remain unclear. In this study, the chemical composition of the water extract of R. serra was analyzed using ultra performance liquid chromatography coupled with a hybrid linear ion trap quadrupole-orbitrap mass spectrometer (UPLC-LTQ-Orbitrap-MS). A total of 46 compounds, comprising ent-kaurane diterpenoids, flavonoids, phenolic acids, and steroids, were identified in the water extract of R. serra, and the extract could significantly alleviate dextran sulfate sodium salt-induced colitis by improving colon length, upregulating anti-inflammatory factors, downregulating proinflammatory factors, and restoring the balance of T helper 17/T regulatory cells. R. serra also preserved intestinal barrier function by increasing the level of tight junction proteins (zonula occludens 1 and occludin) in mouse colonic tissue. In addition, R. serra modulated the gut microbiota composition by increasing bacterial richness and diversity, increasing the abundance of beneficial bacteria (Muribaculaceae, Bacteroides, Lactobacillus, and Prevotellaceae_UCG-001), and decreasing the abundance of pathogenic bacteria (Turicibacter, Eubacterium_fissicatena_group, and Eubacterium_xylanophilum_group). Gut microbiota depletion by antibiotics further confirmed that R. serra alleviated colitis in a microbiota-dependent manner. Overall, our findings provide chemical and biological evidence for the potential application of R. serra in the management of colitis.
Rabdosia serra (R. serra), an important component of Chinese herbal tea, has traditionally been used to treat hepatitis, jaundice, cholecystitis, and colitis. However, the chemical composition of R. serra and its effect against colitis remain unclear. In this study, the chemical composition of the water extract of R. serra was analyzed using ultra performance liquid chromatography coupled with a hybrid linear ion trap quadrupole-orbitrap mass spectrometer (UPLC-LTQ-Orbitrap-MS). A total of 46 compounds, comprising ent-kaurane diterpenoids, flavonoids, phenolic acids, and steroids, were identified in the water extract of R. serra, and the extract could significantly alleviate dextran sulfate sodium salt-induced colitis by improving colon length, upregulating anti-inflammatory factors, downregulating proinflammatory factors, and restoring the balance of T helper 17/T regulatory cells. R. serra also preserved intestinal barrier function by increasing the level of tight junction proteins (zonula occludens 1 and occludin) in mouse colonic tissue. In addition, R. serra modulated the gut microbiota composition by increasing bacterial richness and diversity, increasing the abundance of beneficial bacteria (Muribaculaceae, Bacteroides, Lactobacillus, and Prevotellaceae_UCG-001), and decreasing the abundance of pathogenic bacteria (Turicibacter, Eubacterium_fissicatena_group, and Eubacterium_xylanophilum_group). Gut microbiota depletion by antibiotics further confirmed that R. serra alleviated colitis in a microbiota-dependent manner. Overall, our findings provide chemical and biological evidence for the potential application of R. serra in the management of colitis.
2023, 13(5): 431-441.
doi: 10.1016/j.jpha.2023.03.008
摘要：
DNA barcoding has been widely used for herb identification in recent decades, enabling safety and innovation in the field of herbal medicine. In this article, we summarize recent progress in DNA barcoding for herbal medicine to provide ideas for the further development and application of this technology. Most importantly, the standard DNA barcode has been extended in two ways. First, while conventional DNA barcodes have been widely promoted for their versatility in the identification of fresh or well-preserved samples, super-barcodes based on plastid genomes have rapidly developed and have shown advantages in species identification at low taxonomic levels. Second, mini-barcodes are attractive because they perform better in cases of degraded DNA from herbal materials. In addition, some molecular techniques, such as high-throughput sequencing and isothermal amplification, are combined with DNA barcodes for species identification, which has expanded the applications of herb identification based on DNA barcoding and brought about the post-DNA-barcoding era. Furthermore, standard and high-species coverage DNA barcode reference libraries have been constructed to provide reference sequences for species identification, which increases the accuracy and credibility of species discrimination based on DNA barcodes. In summary, DNA barcoding should play a key role in the quality control of traditional herbal medicine and in the international herb trade.
DNA barcoding has been widely used for herb identification in recent decades, enabling safety and innovation in the field of herbal medicine. In this article, we summarize recent progress in DNA barcoding for herbal medicine to provide ideas for the further development and application of this technology. Most importantly, the standard DNA barcode has been extended in two ways. First, while conventional DNA barcodes have been widely promoted for their versatility in the identification of fresh or well-preserved samples, super-barcodes based on plastid genomes have rapidly developed and have shown advantages in species identification at low taxonomic levels. Second, mini-barcodes are attractive because they perform better in cases of degraded DNA from herbal materials. In addition, some molecular techniques, such as high-throughput sequencing and isothermal amplification, are combined with DNA barcodes for species identification, which has expanded the applications of herb identification based on DNA barcoding and brought about the post-DNA-barcoding era. Furthermore, standard and high-species coverage DNA barcode reference libraries have been constructed to provide reference sequences for species identification, which increases the accuracy and credibility of species discrimination based on DNA barcodes. In summary, DNA barcoding should play a key role in the quality control of traditional herbal medicine and in the international herb trade.
2024, 14(11): 100959.
doi: 10.1016/j.jpha.2024.02.013
摘要：
An optical biosensor is a specialized analytical device that utilizes the principles of optics and light in bimolecular processes. Localized surface plasmon resonance (LSPR) is a phenomenon in the realm of nanophotonics that occurs when metallic nanoparticles (NPs) or nanostructures interact with incident light. Conversely, surface-enhanced Raman spectroscopy (SERS) is an influential analytical technique based on Raman scattering, wherein it amplifies the Raman signals of molecules when they are situated near specific and specially designed nanostructures. A detailed exploration of the recent ground-breaking developments in optical biosensors employing LSPR and SERS technologies has been thoroughly discussed along with their underlying principles and the working mechanisms. A biosensor chip has been created, featuring a high-density deposition of gold nanoparticles (AuNPs) under varying ligand concentration and reaction duration on the substrate. An ordinary description, along with a visual illustration, has been thoroughly provided for concepts such as a sensogram, refractive index shift, surface plasmon resonance (SPR), and the evanescent field, Rayleigh scattering, Raman scattering, as well as the electromagnetic enhancement and chemical enhancement. LSPR and SERS both have advantages and disadvantages, but widely used SERS has some advantages over LSPR, like chemical specificity, high sensitivity, multiplexing, and versatility in different fields. This review confirms and elucidates the significance of different disease biomarker identification. LSPR and SERS both play a vital role in the detection of various types of cancer, such as cervical cancer, ovarian cancer, endometrial cancer, prostate cancer, colorectal cancer, and brain tumors. This proposed optical biosensor offers potential applications for early diagnosis and monitoring of viral disease, bacterial infectious diseases, fungal diseases, diabetes, and cardiac disease biosensing. LSPR and SERS provide a new direction for environmental monitoring, food safety, refining impurities from water samples, and lead detection. The understanding of these biosensors is still limited and challenging.
An optical biosensor is a specialized analytical device that utilizes the principles of optics and light in bimolecular processes. Localized surface plasmon resonance (LSPR) is a phenomenon in the realm of nanophotonics that occurs when metallic nanoparticles (NPs) or nanostructures interact with incident light. Conversely, surface-enhanced Raman spectroscopy (SERS) is an influential analytical technique based on Raman scattering, wherein it amplifies the Raman signals of molecules when they are situated near specific and specially designed nanostructures. A detailed exploration of the recent ground-breaking developments in optical biosensors employing LSPR and SERS technologies has been thoroughly discussed along with their underlying principles and the working mechanisms. A biosensor chip has been created, featuring a high-density deposition of gold nanoparticles (AuNPs) under varying ligand concentration and reaction duration on the substrate. An ordinary description, along with a visual illustration, has been thoroughly provided for concepts such as a sensogram, refractive index shift, surface plasmon resonance (SPR), and the evanescent field, Rayleigh scattering, Raman scattering, as well as the electromagnetic enhancement and chemical enhancement. LSPR and SERS both have advantages and disadvantages, but widely used SERS has some advantages over LSPR, like chemical specificity, high sensitivity, multiplexing, and versatility in different fields. This review confirms and elucidates the significance of different disease biomarker identification. LSPR and SERS both play a vital role in the detection of various types of cancer, such as cervical cancer, ovarian cancer, endometrial cancer, prostate cancer, colorectal cancer, and brain tumors. This proposed optical biosensor offers potential applications for early diagnosis and monitoring of viral disease, bacterial infectious diseases, fungal diseases, diabetes, and cardiac disease biosensing. LSPR and SERS provide a new direction for environmental monitoring, food safety, refining impurities from water samples, and lead detection. The understanding of these biosensors is still limited and challenging.
2022, 12(2): 193-204.
doi: 10.1016/j.jpha.2021.12.006
摘要：
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which caused the coronavirus disease 2019 (COVID-19) pandemic, has affected more than 400 million people worldwide. With the recent rise of new Delta and Omicron variants, the efficacy of the vaccines has become an important question. The goal of various studies has been to limit the spread of the virus by utilizing wireless sensing technologies to prevent human-to-human interactions, particularly for healthcare workers. In this paper, we discuss the current literature on invasive/contact and non-invasive/non-contact technologies (including Wi-Fi, radar, and software-defined radio) that have been effectively used to detect, diagnose, and monitor human activities and COVID-19 related symptoms, such as irregular respiration. In addition, we focused on cutting-edge machine learning algorithms (such as generative adversarial networks, random forest, multilayer perceptron, support vector machine, extremely randomized trees, and k-nearest neighbors) and their essential role in intelligent healthcare systems. Furthermore, this study highlights the limitations related to non-invasive techniques and prospective research directions.
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which caused the coronavirus disease 2019 (COVID-19) pandemic, has affected more than 400 million people worldwide. With the recent rise of new Delta and Omicron variants, the efficacy of the vaccines has become an important question. The goal of various studies has been to limit the spread of the virus by utilizing wireless sensing technologies to prevent human-to-human interactions, particularly for healthcare workers. In this paper, we discuss the current literature on invasive/contact and non-invasive/non-contact technologies (including Wi-Fi, radar, and software-defined radio) that have been effectively used to detect, diagnose, and monitor human activities and COVID-19 related symptoms, such as irregular respiration. In addition, we focused on cutting-edge machine learning algorithms (such as generative adversarial networks, random forest, multilayer perceptron, support vector machine, extremely randomized trees, and k-nearest neighbors) and their essential role in intelligent healthcare systems. Furthermore, this study highlights the limitations related to non-invasive techniques and prospective research directions.
2023, 13(2): 111-126.
doi: 10.1016/j.jpha.2022.12.004
摘要：
Similar to blood, interstitial fluid (ISF) contains exogenous drugs and biomarkers and may therefore substitute blood in drug analysis. However, current ISF extraction techniques require bulky instruments and are both time-consuming and complicated, which has inspired the development of viable alternatives such as those relying on skin or tissue puncturing with microneedles. Currently, microneedles are widely employed for transdermal drug delivery and have been successfully used for ISF extraction by different mechanisms to facilitate subsequent analysis. The integration of microneedles with sensors enables in situ ISF analysis and specific compound monitoring, while the integration of monitoring and delivery functions in wearable devices allows real-time dose modification. Herein, we review the progress in drug analysis based on microneedle-assisted ISF extraction and discuss the related future opportunities and challenges.
Similar to blood, interstitial fluid (ISF) contains exogenous drugs and biomarkers and may therefore substitute blood in drug analysis. However, current ISF extraction techniques require bulky instruments and are both time-consuming and complicated, which has inspired the development of viable alternatives such as those relying on skin or tissue puncturing with microneedles. Currently, microneedles are widely employed for transdermal drug delivery and have been successfully used for ISF extraction by different mechanisms to facilitate subsequent analysis. The integration of microneedles with sensors enables in situ ISF analysis and specific compound monitoring, while the integration of monitoring and delivery functions in wearable devices allows real-time dose modification. Herein, we review the progress in drug analysis based on microneedle-assisted ISF extraction and discuss the related future opportunities and challenges.
2023, 13(8): 836-850.
doi: 10.1016/j.jpha.2023.06.011
摘要：
Bioinformatic analysis of large and complex omics datasets has become increasingly useful in modern day biology by providing a great depth of information, with its application to neuroscience termed neuroinformatics. Data mining of omics datasets has enabled the generation of new hypotheses based on differentially regulated biological molecules associated with disease mechanisms, which can be tested experimentally for improved diagnostic and therapeutic targeting of neurodegenerative diseases. Importantly, integrating multi-omics data using a systems bioinformatics approach will advance the understanding of the layered and interactive network of biological regulation that exchanges systemic knowledge to facilitate the development of a comprehensive human brain profile. In this review, we first summarize data mining studies utilizing datasets from the individual type of omics analysis, including epigenetics/epigenomics, transcriptomics, proteomics, metabolomics, lipidomics, and spatial omics, pertaining to Alzheimer's disease, Parkinson's disease, and multiple sclerosis. We then discuss multi-omics integration approaches, including independent biological integration and unsupervised integration methods, for more intuitive and informative interpretation of the biological data obtained across different omics layers. We further assess studies that integrate multi-omics in data mining which provide convoluted biological insights and offer proof-of-concept proposition towards systems bioinformatics in the reconstruction of brain networks. Finally, we recommend a combination of high dimensional bioinformatics analysis with experimental validation to achieve translational neuroscience applications including biomarker discovery, therapeutic development, and elucidation of disease mechanisms. We conclude by providing future perspectives and opportunities in applying integrative multi-omics and systems bioinformatics to achieve precision phenotyping of neurodegenerative diseases and towards personalized medicine.
Bioinformatic analysis of large and complex omics datasets has become increasingly useful in modern day biology by providing a great depth of information, with its application to neuroscience termed neuroinformatics. Data mining of omics datasets has enabled the generation of new hypotheses based on differentially regulated biological molecules associated with disease mechanisms, which can be tested experimentally for improved diagnostic and therapeutic targeting of neurodegenerative diseases. Importantly, integrating multi-omics data using a systems bioinformatics approach will advance the understanding of the layered and interactive network of biological regulation that exchanges systemic knowledge to facilitate the development of a comprehensive human brain profile. In this review, we first summarize data mining studies utilizing datasets from the individual type of omics analysis, including epigenetics/epigenomics, transcriptomics, proteomics, metabolomics, lipidomics, and spatial omics, pertaining to Alzheimer's disease, Parkinson's disease, and multiple sclerosis. We then discuss multi-omics integration approaches, including independent biological integration and unsupervised integration methods, for more intuitive and informative interpretation of the biological data obtained across different omics layers. We further assess studies that integrate multi-omics in data mining which provide convoluted biological insights and offer proof-of-concept proposition towards systems bioinformatics in the reconstruction of brain networks. Finally, we recommend a combination of high dimensional bioinformatics analysis with experimental validation to achieve translational neuroscience applications including biomarker discovery, therapeutic development, and elucidation of disease mechanisms. We conclude by providing future perspectives and opportunities in applying integrative multi-omics and systems bioinformatics to achieve precision phenotyping of neurodegenerative diseases and towards personalized medicine.
2022, 12(3): 489-499.
doi: 10.1016/j.jpha.2021.09.003
摘要：
In order to better control the quality of Flos Puerariae (FP), qualitative and quantitative analyses were initially performed by using chemical fingerprint and chemometrics methods in this study. First, the fingerprint of FP was developed by HPLC and the chemical markers were screened out by similarity analysis (SA), hierarchical clustering analysis (HCA), principal components analysis (PCA), and orthogonal partial least squares discriminant analysis (OPLS-DA). Next, the chemical constituents in FP were profiled and identified by HPLC coupled to Fourier transform ion cyclotron resonance mass spectrometry (HPLC-FT-ICR MS). Then, the characteristic constituents in FP were quantitatively analyzed by HPLC. As a result, 31 common peaks were assigned in the fingerprint and 6 of them were considered as qualitative markers. A total of 35 chemical constituents were detected by HPLC-FT-ICR MS and 16 of them were unambiguously identified by comparing retention time, UV absorption wavelength, accurate mass, and MS/MS data with those of reference standards. Subsequently, the contents of glycitin, genistin, tectoridin, glycitein, genistein, and tectorigenin in 13 batches of FP were detected, ranging from 0.4438 to 11.06 mg/g, 0.955 to 1.726 mg/g, 9.81 to 57.22 mg/g, 3.349 to 41.60 mg/g, 0.3576 to 0.989 mg/g, and 2.126 to 9.99 mg/g, respectively. In conclusion, fingerprint analysis in combination with chemometrics methods could discover chemical markers for improving the quality control standard of FP. It is expected that the strategy applied in this study will be valuable for further quality control of other traditional Chinese medicines.
In order to better control the quality of Flos Puerariae (FP), qualitative and quantitative analyses were initially performed by using chemical fingerprint and chemometrics methods in this study. First, the fingerprint of FP was developed by HPLC and the chemical markers were screened out by similarity analysis (SA), hierarchical clustering analysis (HCA), principal components analysis (PCA), and orthogonal partial least squares discriminant analysis (OPLS-DA). Next, the chemical constituents in FP were profiled and identified by HPLC coupled to Fourier transform ion cyclotron resonance mass spectrometry (HPLC-FT-ICR MS). Then, the characteristic constituents in FP were quantitatively analyzed by HPLC. As a result, 31 common peaks were assigned in the fingerprint and 6 of them were considered as qualitative markers. A total of 35 chemical constituents were detected by HPLC-FT-ICR MS and 16 of them were unambiguously identified by comparing retention time, UV absorption wavelength, accurate mass, and MS/MS data with those of reference standards. Subsequently, the contents of glycitin, genistin, tectoridin, glycitein, genistein, and tectorigenin in 13 batches of FP were detected, ranging from 0.4438 to 11.06 mg/g, 0.955 to 1.726 mg/g, 9.81 to 57.22 mg/g, 3.349 to 41.60 mg/g, 0.3576 to 0.989 mg/g, and 2.126 to 9.99 mg/g, respectively. In conclusion, fingerprint analysis in combination with chemometrics methods could discover chemical markers for improving the quality control standard of FP. It is expected that the strategy applied in this study will be valuable for further quality control of other traditional Chinese medicines.
2022, 12(5): 725-732.
doi: 10.1016/j.jpha.2022.05.006
摘要：
Astragali Radix (AR) is a clinically used herbal medicine with multiple immunomodulatory activities that can strengthen the activity and cytotoxicity of natural killer (NK) cells. However, owing to the complexity of its composition, the specific active ingredients in AR that act on NK cells are not clear yet. Cell membrane chromatography (CMC) is mainly used to screen the active ingredients in a complex system of herbal medicines. In this study, a new comprehensive two-dimensional (2D) NK-92MI CMC/C18 column/time-of-flight mass spectrometry (TOFMS) system was established to screen for potential NK cell activators. To obtain a higher column efficiency, 3-mercaptopropyltrimethoxysilane-modified silica was synthesized to prepare the NK-92MI CMC column. In total, nine components in AR were screened from this system, which could be washed out from the NK-92MI/CMC column after 10 min, and they showed good affinity for NK-92MI/CMC column. Two representative active compounds of AR, isoastragaloside I and astragaloside IV, promoted the killing effect of NK cells on K562 cells in a dose-dependent manner. It can thus suggest that isoastragaloside I and astragaloside IV are the main immunomodulatory components of AR. This comprehensive 2D NK-92MI CMC analytical system is a practical method for screening immune cell activators from other herbal medicines with immunomodulatory effects.
Astragali Radix (AR) is a clinically used herbal medicine with multiple immunomodulatory activities that can strengthen the activity and cytotoxicity of natural killer (NK) cells. However, owing to the complexity of its composition, the specific active ingredients in AR that act on NK cells are not clear yet. Cell membrane chromatography (CMC) is mainly used to screen the active ingredients in a complex system of herbal medicines. In this study, a new comprehensive two-dimensional (2D) NK-92MI CMC/C18 column/time-of-flight mass spectrometry (TOFMS) system was established to screen for potential NK cell activators. To obtain a higher column efficiency, 3-mercaptopropyltrimethoxysilane-modified silica was synthesized to prepare the NK-92MI CMC column. In total, nine components in AR were screened from this system, which could be washed out from the NK-92MI/CMC column after 10 min, and they showed good affinity for NK-92MI/CMC column. Two representative active compounds of AR, isoastragaloside I and astragaloside IV, promoted the killing effect of NK cells on K562 cells in a dose-dependent manner. It can thus suggest that isoastragaloside I and astragaloside IV are the main immunomodulatory components of AR. This comprehensive 2D NK-92MI CMC analytical system is a practical method for screening immune cell activators from other herbal medicines with immunomodulatory effects.
2023, 13(5): 463-482.
doi: 10.1016/j.jpha.2023.03.006
摘要：
Hepatocellular carcinoma (HCC) is the third leading cause of cancer death worldwide. Ginsenoside Rk3, an important and rare saponin in heat-treated ginseng, is generated from Rg1 and has a smaller molecular weight. However, the anti-HCC efficacy and mechanisms of ginsenoside Rk3 have not yet been characterized. Here, we investigated the mechanism by which ginsenoside Rk3, a tetracyclic triterpenoid rare ginsenoside, inhibits the growth of HCC. We first explored the possible potential targets of Rk3 through network pharmacology. Both in vitro (HepG2 and HCC-LM3 cells) and in vivo (primary liver cancer mice and HCC-LM3 subcutaneous tumor-bearing mice) studies revealed that Rk3 significantly inhibits the proliferation of HCC. Meanwhile, Rk3 blocked the cell cycle in HCC at the G1 phase and induced autophagy and apoptosis in HCC. Further proteomics and siRNA experiments showed that Rk3 regulates the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) pathway to inhibit HCC growth, which was validated by molecular docking and surface plasmon resonance. In conclusion, we report the discovery that ginsenoside Rk3 binds to PI3K/AKT and promotes autophagy and apoptosis in HCC. Our data strongly support the translation of ginsenoside Rk3 into novel PI3K/AKT-targeting therapeutics for HCC treatment with low toxic side effects.
Hepatocellular carcinoma (HCC) is the third leading cause of cancer death worldwide. Ginsenoside Rk3, an important and rare saponin in heat-treated ginseng, is generated from Rg1 and has a smaller molecular weight. However, the anti-HCC efficacy and mechanisms of ginsenoside Rk3 have not yet been characterized. Here, we investigated the mechanism by which ginsenoside Rk3, a tetracyclic triterpenoid rare ginsenoside, inhibits the growth of HCC. We first explored the possible potential targets of Rk3 through network pharmacology. Both in vitro (HepG2 and HCC-LM3 cells) and in vivo (primary liver cancer mice and HCC-LM3 subcutaneous tumor-bearing mice) studies revealed that Rk3 significantly inhibits the proliferation of HCC. Meanwhile, Rk3 blocked the cell cycle in HCC at the G1 phase and induced autophagy and apoptosis in HCC. Further proteomics and siRNA experiments showed that Rk3 regulates the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) pathway to inhibit HCC growth, which was validated by molecular docking and surface plasmon resonance. In conclusion, we report the discovery that ginsenoside Rk3 binds to PI3K/AKT and promotes autophagy and apoptosis in HCC. Our data strongly support the translation of ginsenoside Rk3 into novel PI3K/AKT-targeting therapeutics for HCC treatment with low toxic side effects.
2023, 13(12): 1388-1407.
doi: 10.1016/j.jpha.2023.07.012
摘要：
In traditional medicine and ethnomedicine, medicinal plants have long been recognized as the basis for materials in therapeutic applications worldwide. In particular, the remarkable curative effect of traditional Chinese medicine during corona virus disease 2019 (COVID-19) pandemic has attracted extensive attention globally. Medicinal plants have, therefore, become increasingly popular among the public. However, with increasing demand for and profit with medicinal plants, commercial fraudulent events such as adulteration or counterfeits sometimes occur, which poses a serious threat to the clinical outcomes and interests of consumers. With rapid advances in artificial intelligence, machine learning can be used to mine information on various medicinal plants to establish an ideal resource database. We herein present a review that mainly introduces common machine learning algorithms and discusses their application in multi-source data analysis of medicinal plants. The combination of machine learning algorithms and multi-source data analysis facilitates a comprehensive analysis and aids in the effective evaluation of the quality of medicinal plants. The findings of this review provide new possibilities for promoting the development and utilization of medicinal plants.
In traditional medicine and ethnomedicine, medicinal plants have long been recognized as the basis for materials in therapeutic applications worldwide. In particular, the remarkable curative effect of traditional Chinese medicine during corona virus disease 2019 (COVID-19) pandemic has attracted extensive attention globally. Medicinal plants have, therefore, become increasingly popular among the public. However, with increasing demand for and profit with medicinal plants, commercial fraudulent events such as adulteration or counterfeits sometimes occur, which poses a serious threat to the clinical outcomes and interests of consumers. With rapid advances in artificial intelligence, machine learning can be used to mine information on various medicinal plants to establish an ideal resource database. We herein present a review that mainly introduces common machine learning algorithms and discusses their application in multi-source data analysis of medicinal plants. The combination of machine learning algorithms and multi-source data analysis facilitates a comprehensive analysis and aids in the effective evaluation of the quality of medicinal plants. The findings of this review provide new possibilities for promoting the development and utilization of medicinal plants.
2023, 13(2): 216-222.
doi: 10.1016/j.jpha.2022.10.004
摘要：
The direct coupling of solid-phase microextraction (SPME) to mass spectrometry (MS) (SPME-MS) has proven to be an effective method for the fast screening and quantitative analysis of compounds in complex matrices such as blood and plasma. In recent years, our lab has developed three novel SPME-MS techniques: SPME-microfluidic open interface-MS (SPME-MOI-MS), coated blade spray-MS (CBS-MS), and SPME-probe electrospray ionization-MS (SPME-PESI-MS). The fast and high-throughput nature of these SPME-MS technologies makes them attractive options for point-of-care analysis and anti-doping testing. However, all these three techniques utilize different SPME geometries and were tested with different MS instruments. Lack of comparative data makes it difficult to determine which of these methodologies is the best option for any given application. This work fills this gap by making a comprehensive comparison of these three technologies with different SPME devices including SPME fibers, CBS blades, and SPME-PESI probes and SPME-liquid chromatography-MS (SPME-LC-MS) for the analysis of drugs of abuse using the same MS instrument. Furthermore, for the first time, we developed different desorption chambers for MOI-MS for coupling with SPME fibers, CBS blades, and SPME-PESI probes, thus illustrating the universality of this approach. In total, eight analytical methods were developed, with the experimental data showing that all the SPME-based methods provided good analytical performance with R2 of linearities larger than 0.9925, accuracies between 81% and 118%, and good precision with an RSD%≤13%.
The direct coupling of solid-phase microextraction (SPME) to mass spectrometry (MS) (SPME-MS) has proven to be an effective method for the fast screening and quantitative analysis of compounds in complex matrices such as blood and plasma. In recent years, our lab has developed three novel SPME-MS techniques: SPME-microfluidic open interface-MS (SPME-MOI-MS), coated blade spray-MS (CBS-MS), and SPME-probe electrospray ionization-MS (SPME-PESI-MS). The fast and high-throughput nature of these SPME-MS technologies makes them attractive options for point-of-care analysis and anti-doping testing. However, all these three techniques utilize different SPME geometries and were tested with different MS instruments. Lack of comparative data makes it difficult to determine which of these methodologies is the best option for any given application. This work fills this gap by making a comprehensive comparison of these three technologies with different SPME devices including SPME fibers, CBS blades, and SPME-PESI probes and SPME-liquid chromatography-MS (SPME-LC-MS) for the analysis of drugs of abuse using the same MS instrument. Furthermore, for the first time, we developed different desorption chambers for MOI-MS for coupling with SPME fibers, CBS blades, and SPME-PESI probes, thus illustrating the universality of this approach. In total, eight analytical methods were developed, with the experimental data showing that all the SPME-based methods provided good analytical performance with R2 of linearities larger than 0.9925, accuracies between 81% and 118%, and good precision with an RSD%≤13%.
2022, 12(2): 221-231.
doi: 10.1016/j.jpha.2021.11.004
摘要：
Breast cancer is one of the leading causes of cancer-related deaths in women worldwide. It is a cancer that originates from the mammary ducts and involves mutations in multiple genes. Recently, the treatment of breast cancer has become increasingly challenging owing to the increase in tumor heterogeneity and aggressiveness, which gives rise to therapeutic resistance. Epidemiological, population-based, and hospital-based case-control studies have demonstrated an association between high intake of certain Allium vegetables and a reduced risk in the development of breast cancer. Diallyl disulfide (DADS) and diallyl trisulfide (DATS) are the main allyl sulfur compounds present in garlic, and are known to exhibit anticancer activity as they interfere with breast cancer cell proliferation, tumor metastasis, and angiogenesis. The present review highlights multidrug resistance mechanisms and their signaling pathways in breast cancer. This review discusses the potential anticancer activities of DADS and DATS, with emphasis on drug resistance in triple-negative breast cancer (TNBC). Understanding the anticancer activities of DADS and DATS provides insights into their potential in targeting drug resistance mechanisms of TNBC, especially in clinical studies.
Breast cancer is one of the leading causes of cancer-related deaths in women worldwide. It is a cancer that originates from the mammary ducts and involves mutations in multiple genes. Recently, the treatment of breast cancer has become increasingly challenging owing to the increase in tumor heterogeneity and aggressiveness, which gives rise to therapeutic resistance. Epidemiological, population-based, and hospital-based case-control studies have demonstrated an association between high intake of certain Allium vegetables and a reduced risk in the development of breast cancer. Diallyl disulfide (DADS) and diallyl trisulfide (DATS) are the main allyl sulfur compounds present in garlic, and are known to exhibit anticancer activity as they interfere with breast cancer cell proliferation, tumor metastasis, and angiogenesis. The present review highlights multidrug resistance mechanisms and their signaling pathways in breast cancer. This review discusses the potential anticancer activities of DADS and DATS, with emphasis on drug resistance in triple-negative breast cancer (TNBC). Understanding the anticancer activities of DADS and DATS provides insights into their potential in targeting drug resistance mechanisms of TNBC, especially in clinical studies.
2022, 12(3): 436-445.
doi: 10.1016/j.jpha.2021.08.005
摘要：
As the most commonly used antipyretic and analgesic drug, paracetamol (PA) coexists with neurotransmitter dopamine (DA) in real biological samples. Their simultaneous determination is extremely important for human health, but they also interfere with each other. In order to improve the conductivity, adsorption affinity, sensitivity, and selectivity of TiO2-based electrochemical sensor, N-doped carbon@TiO2 double-shelled hollow sphere (H-C/N@TiO2) is designed and synthesized by simple alcoholic and hydrothermal method, using polystyrene sphere (PS) as a template. Meanwhile, TiO2 hollow spheres (H-TiO2) or N-doped carbon hollow spheres (H-C/N) are also prepared by the same method. H-C/N@TiO2 has good conductivity, charge separation, and the highly enhanced and stable current responses for the detection of PA and DA. The detection limit and linear range are 50.0 nmol/L and 0.3-50 μmol/L for PA, 40.0 nmol/L and 0.3-50 μmol/L for DA, respectively, which are better than those of carbon-based sensors. Moreover, this electrochemical sensor, with high selectivity, strong anti-interference, high reliability, and long time durability, can be used for the simultaneous detection of PA and DA in human blood serum and saliva. The high electrochemical performance of H-C/N@TiO2 is attributed to the multi-functional combination of different layers, because of good conductivity, absorption and electrons transfer ability from in-situ N-doped carbon and electrocatalytic activity from TiO2.
As the most commonly used antipyretic and analgesic drug, paracetamol (PA) coexists with neurotransmitter dopamine (DA) in real biological samples. Their simultaneous determination is extremely important for human health, but they also interfere with each other. In order to improve the conductivity, adsorption affinity, sensitivity, and selectivity of TiO2-based electrochemical sensor, N-doped carbon@TiO2 double-shelled hollow sphere (H-C/N@TiO2) is designed and synthesized by simple alcoholic and hydrothermal method, using polystyrene sphere (PS) as a template. Meanwhile, TiO2 hollow spheres (H-TiO2) or N-doped carbon hollow spheres (H-C/N) are also prepared by the same method. H-C/N@TiO2 has good conductivity, charge separation, and the highly enhanced and stable current responses for the detection of PA and DA. The detection limit and linear range are 50.0 nmol/L and 0.3-50 μmol/L for PA, 40.0 nmol/L and 0.3-50 μmol/L for DA, respectively, which are better than those of carbon-based sensors. Moreover, this electrochemical sensor, with high selectivity, strong anti-interference, high reliability, and long time durability, can be used for the simultaneous detection of PA and DA in human blood serum and saliva. The high electrochemical performance of H-C/N@TiO2 is attributed to the multi-functional combination of different layers, because of good conductivity, absorption and electrons transfer ability from in-situ N-doped carbon and electrocatalytic activity from TiO2.
2023, 13(4): 340-354.
doi: 10.1016/j.jpha.2023.03.001
摘要：
Liquid biopsy is a technology that exhibits potential to detect cancer early, monitor therapies, and predict cancer prognosis due to its unique characteristics, including noninvasive sampling and real-time analysis. Circulating tumor cells (CTCs) and extracellular vesicles (EVs) are two important components of circulating targets, carrying substantial disease-related molecular information and playing a key role in liquid biopsy. Aptamers are single-stranded oligonucleotides with superior affinity and specificity, and they can bind to targets by folding into unique tertiary structures. Aptamer-based microfluidic platforms offer new ways to enhance the purity and capture efficiency of CTCs and EVs by combining the advantages of microfluidic chips as isolation platforms and aptamers as recognition tools. In this review, we first briefly introduce some new strategies for aptamer discovery based on traditional and aptamer-based microfluidic approaches. Then, we subsequently summarize the progress of aptamer-based microfluidics for CTC and EV detection. Finally, we offer an outlook on the future directional challenges of aptamer-based microfluidics for circulating targets in clinical applications.
Liquid biopsy is a technology that exhibits potential to detect cancer early, monitor therapies, and predict cancer prognosis due to its unique characteristics, including noninvasive sampling and real-time analysis. Circulating tumor cells (CTCs) and extracellular vesicles (EVs) are two important components of circulating targets, carrying substantial disease-related molecular information and playing a key role in liquid biopsy. Aptamers are single-stranded oligonucleotides with superior affinity and specificity, and they can bind to targets by folding into unique tertiary structures. Aptamer-based microfluidic platforms offer new ways to enhance the purity and capture efficiency of CTCs and EVs by combining the advantages of microfluidic chips as isolation platforms and aptamers as recognition tools. In this review, we first briefly introduce some new strategies for aptamer discovery based on traditional and aptamer-based microfluidic approaches. Then, we subsequently summarize the progress of aptamer-based microfluidics for CTC and EV detection. Finally, we offer an outlook on the future directional challenges of aptamer-based microfluidics for circulating targets in clinical applications.
2023, 13(12): 1408-1428.
doi: 10.1016/j.jpha.2023.09.012
摘要：
This review aims to identify in vivo studies investigating the potential of plant substances and their natural molecules in managing inflammatory bowel disease (IBD). Specifically, the objective is to examine the impact of these substances on interleukins and other key inflammatory signaling markers. Relevant articles published up to December 2022 were identified through a search of the PubMed, Scopus, Web of Science, and Embase databases. The search used keywords including “inflammatory bowel disease”, “medicinal plants”, “natural molecules”, “anti-inflammatory”, and “ulcerative colitis”, and identified 1,878 potentially relevant articles, of which 89 were included in this review after completion of the selection process. This study provides preclinical data on natural products (NPs) that can potentially treat IBD, including ulcerative colitis. The main actions of these NPs relate to their effects on nuclear factor kappa B (NF-κB), the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling pathway, the regulation of T helper 17/regulatory T cells balance, and oxidative stress. The ability of these NPs to inhibit intestinal inflammation appears to be dependent on lowering levels of the pro-inflammatory cytokines tumor necrosis factor-alpha (TNF-α), interleukin (IL)-1β, and IL-17, via the Jun N-terminal kinase (JNK)1, NF-κβ-p65, and STAT3 pathways. In addition, NPs were shown to reduce oxidative stress and the severity of ulcerative colitis, as well as increase the activity of antioxidant enzymes. These actions suggest that NPs represent a promising treatment for IBD, and potentially have greater efficacy and safety than current treatments.
This review aims to identify in vivo studies investigating the potential of plant substances and their natural molecules in managing inflammatory bowel disease (IBD). Specifically, the objective is to examine the impact of these substances on interleukins and other key inflammatory signaling markers. Relevant articles published up to December 2022 were identified through a search of the PubMed, Scopus, Web of Science, and Embase databases. The search used keywords including “inflammatory bowel disease”, “medicinal plants”, “natural molecules”, “anti-inflammatory”, and “ulcerative colitis”, and identified 1,878 potentially relevant articles, of which 89 were included in this review after completion of the selection process. This study provides preclinical data on natural products (NPs) that can potentially treat IBD, including ulcerative colitis. The main actions of these NPs relate to their effects on nuclear factor kappa B (NF-κB), the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling pathway, the regulation of T helper 17/regulatory T cells balance, and oxidative stress. The ability of these NPs to inhibit intestinal inflammation appears to be dependent on lowering levels of the pro-inflammatory cytokines tumor necrosis factor-alpha (TNF-α), interleukin (IL)-1β, and IL-17, via the Jun N-terminal kinase (JNK)1, NF-κβ-p65, and STAT3 pathways. In addition, NPs were shown to reduce oxidative stress and the severity of ulcerative colitis, as well as increase the activity of antioxidant enzymes. These actions suggest that NPs represent a promising treatment for IBD, and potentially have greater efficacy and safety than current treatments.
Celastrol targeting Nedd4 reduces Nrf2-mediated oxidative stress in astrocytes after ischemic stroke
2023, 13(2): 156-169.
doi: 10.1016/j.jpha.2022.12.002
摘要：
Stroke is the second leading cause of death worldwide, and oxidative stress plays a crucial role. Celastrol exhibits strong antioxidant properties in several diseases; however, whether it can affect oxidation in cerebral ischemic-reperfusion injury (CIRI) remains unclear. This study aimed to determine whether celastrol could reduce oxidative damage during CIRI and to elucidate the underlying mechanisms. Here, we found that celastrol attenuated oxidative injury in CIRI by upregulating nuclear factor E2-related factor 2 (Nrf2). Using alkynyl-tagged celastrol and liquid chromatography-tandem mass spectrometry, we showed that celastrol directly bound to neuronally expressed developmentally downregulated 4 (Nedd4) and then released Nrf2 from Nedd4 in astrocytes. Nedd4 promoted the degradation of Nrf2 through K48-linked ubiquitination and thus contributed to astrocytic reactive oxygen species production in CIRI, which was significantly blocked by celastrol. Furthermore, by inhibiting oxidative stress and astrocyte activation, celastrol effectively rescued neurons from axon damage and apoptosis. Our study uncovered Nedd4 as a direct target of celastrol, and that celastrol exerts an antioxidative effect on astrocytes by inhibiting the interaction between Nedd4 and Nrf2 and reducing Nrf2 degradation in CIRI.
Stroke is the second leading cause of death worldwide, and oxidative stress plays a crucial role. Celastrol exhibits strong antioxidant properties in several diseases; however, whether it can affect oxidation in cerebral ischemic-reperfusion injury (CIRI) remains unclear. This study aimed to determine whether celastrol could reduce oxidative damage during CIRI and to elucidate the underlying mechanisms. Here, we found that celastrol attenuated oxidative injury in CIRI by upregulating nuclear factor E2-related factor 2 (Nrf2). Using alkynyl-tagged celastrol and liquid chromatography-tandem mass spectrometry, we showed that celastrol directly bound to neuronally expressed developmentally downregulated 4 (Nedd4) and then released Nrf2 from Nedd4 in astrocytes. Nedd4 promoted the degradation of Nrf2 through K48-linked ubiquitination and thus contributed to astrocytic reactive oxygen species production in CIRI, which was significantly blocked by celastrol. Furthermore, by inhibiting oxidative stress and astrocyte activation, celastrol effectively rescued neurons from axon damage and apoptosis. Our study uncovered Nedd4 as a direct target of celastrol, and that celastrol exerts an antioxidative effect on astrocytes by inhibiting the interaction between Nedd4 and Nrf2 and reducing Nrf2 degradation in CIRI.
2023, 13(4): 323-339.
doi: 10.1016/j.jpha.2023.01.003
摘要：
Capillary electrochromatography (CEC) plays a significant role in chiral separation via the double separation principle, partition coefficient difference between the two phases, and electroosmotic flow-driven separation. Given the distinct properties of the inner wall stationary phase (SP), the separation ability of each SP differs from one another. Particularly, it provides large room for promising applications of open tubular capillary electrochromatography (OT-CEC). We divided the OT-CEC SPs developed over the past four years into six types: ionic liquids, nanoparticle materials, microporous materials, biomaterials, non-nanopolymers, and others, to mainly introduce their characteristics in chiral drug separation. There also added a few classic SPs that occurred within ten years as supplements to enrich the features of each SP. Additionally, we discuss their applications in metabolomics, food, cosmetics, environment, and biology as analytes in addition to chiral drugs. OT-CEC plays an increasingly significant role in chiral separation and may promote the development of capillary electrophoresis (CE) combined with other instruments in recent years, such as CE with mass spectrometry (CE/MS) and CE with ultraviolet light detector (CE/UV).
Capillary electrochromatography (CEC) plays a significant role in chiral separation via the double separation principle, partition coefficient difference between the two phases, and electroosmotic flow-driven separation. Given the distinct properties of the inner wall stationary phase (SP), the separation ability of each SP differs from one another. Particularly, it provides large room for promising applications of open tubular capillary electrochromatography (OT-CEC). We divided the OT-CEC SPs developed over the past four years into six types: ionic liquids, nanoparticle materials, microporous materials, biomaterials, non-nanopolymers, and others, to mainly introduce their characteristics in chiral drug separation. There also added a few classic SPs that occurred within ten years as supplements to enrich the features of each SP. Additionally, we discuss their applications in metabolomics, food, cosmetics, environment, and biology as analytes in addition to chiral drugs. OT-CEC plays an increasingly significant role in chiral separation and may promote the development of capillary electrophoresis (CE) combined with other instruments in recent years, such as CE with mass spectrometry (CE/MS) and CE with ultraviolet light detector (CE/UV).
2023, 13(12): 1429-1451.
doi: 10.1016/j.jpha.2023.08.009
摘要：
With the continuous discovery and research of predictive cancer-related biomarkers, liquid biopsy shows great potential in cancer diagnosis. Surface-enhanced Raman scattering (SERS) and microfluidic technology have received much attention among the various cancer biomarker detection methods. The former has ultrahigh detection sensitivity and can provide a unique fingerprint. In contrast, the latter has the characteristics of miniaturization and integration, which can realize accurate control of the detection samples and high-throughput detection through design. Both have the potential for point-of-care testing (POCT), and their combination (lab-on-a-chip SERS (LoC-SERS)) shows good compatibility. In this paper, the basic situation of circulating proteins, circulating tumor cells, exosomes, circulating tumor DNA (ctDNA), and microRNA (miRNA) in the diagnosis of various cancers is reviewed, and the detection research of these biomarkers by the LoC-SERS platform in recent years is described in detail. At the same time, the challenges and future development of the platform are discussed at the end of the review. Summarizing the current technology is expected to provide a reference for scholars engaged in related work and interested in this field.
With the continuous discovery and research of predictive cancer-related biomarkers, liquid biopsy shows great potential in cancer diagnosis. Surface-enhanced Raman scattering (SERS) and microfluidic technology have received much attention among the various cancer biomarker detection methods. The former has ultrahigh detection sensitivity and can provide a unique fingerprint. In contrast, the latter has the characteristics of miniaturization and integration, which can realize accurate control of the detection samples and high-throughput detection through design. Both have the potential for point-of-care testing (POCT), and their combination (lab-on-a-chip SERS (LoC-SERS)) shows good compatibility. In this paper, the basic situation of circulating proteins, circulating tumor cells, exosomes, circulating tumor DNA (ctDNA), and microRNA (miRNA) in the diagnosis of various cancers is reviewed, and the detection research of these biomarkers by the LoC-SERS platform in recent years is described in detail. At the same time, the challenges and future development of the platform are discussed at the end of the review. Summarizing the current technology is expected to provide a reference for scholars engaged in related work and interested in this field.
2022, 12(4): 570-582.
doi: 10.1016/j.jpha.2022.06.001
摘要：
Hepatic stellate cells (HSCs) are essential drivers of fibrogenesis. Inducing activated-HSC apoptosis is a promising strategy for treating hepatic fibrosis. 18beta-glycyrrhetinic acid (18β-GA) is a natural compound that exists widely in herbal medicines, such as Glycyrrhiza uralensis Fisch, which is used for treating multiple liver diseases, especially in Asia. In the present study, we demonstrated that 18β-GA decreased hepatic fibrosis by inducing the apoptosis in activated HSCs. 18β-GA inhibited the expression of α-smooth muscle actin and collagen type I alpha-1. Using a chemoproteomic approach derived from activity-based protein profiling, together with cellular thermal shift assay and surface plasmon resonance, we found that 18β-GA covalently targeted peroxiredoxin 1 (PRDX1) and peroxiredoxin 2 (PRDX2) proteins via binding to active cysteine residues and thereby inhibited their enzymatic activities. 18β-GA induced the elevation of reactive oxygen species (ROS), resulting in the apoptosis of activated HSCs. PRDX1 knockdown also led to ROS-mediated apoptosis in activated HSCs. Collectively, our findings revealed the target proteins and molecular mechanisms of 18β-GA in ameliorating hepatic fibrosis, highlighting the future development of 18β-GA as a novel therapeutic drug for hepatic fibrosis.
Hepatic stellate cells (HSCs) are essential drivers of fibrogenesis. Inducing activated-HSC apoptosis is a promising strategy for treating hepatic fibrosis. 18beta-glycyrrhetinic acid (18β-GA) is a natural compound that exists widely in herbal medicines, such as Glycyrrhiza uralensis Fisch, which is used for treating multiple liver diseases, especially in Asia. In the present study, we demonstrated that 18β-GA decreased hepatic fibrosis by inducing the apoptosis in activated HSCs. 18β-GA inhibited the expression of α-smooth muscle actin and collagen type I alpha-1. Using a chemoproteomic approach derived from activity-based protein profiling, together with cellular thermal shift assay and surface plasmon resonance, we found that 18β-GA covalently targeted peroxiredoxin 1 (PRDX1) and peroxiredoxin 2 (PRDX2) proteins via binding to active cysteine residues and thereby inhibited their enzymatic activities. 18β-GA induced the elevation of reactive oxygen species (ROS), resulting in the apoptosis of activated HSCs. PRDX1 knockdown also led to ROS-mediated apoptosis in activated HSCs. Collectively, our findings revealed the target proteins and molecular mechanisms of 18β-GA in ameliorating hepatic fibrosis, highlighting the future development of 18β-GA as a novel therapeutic drug for hepatic fibrosis.
2025, 15(1): 101046.
doi: 10.1016/j.jpha.2024.101046
摘要：
2022, 12(1): 15-28.
doi: 10.1016/j.jpha.2021.06.009
摘要：
Capillary electrophoresis (CE) is widely used for the impurity profiling of drugs that contain stereochemical centers in their structures, analysis of biomolecules, and characterization of biopharmaceuticals. Currently, CE is the method of choice for the analysis of foodstuffs and the determination of adulterants. This article discusses the general theory and instrumentation of CE as well as the classification of various CE techniques. It also presents an overview of research on the applications of different CE techniques in the impurity profiling of drugs in the past decade. The review briefly presents a comparison between CE and liquid chromatography methods and highlights the strengths of CE using drug compounds as examples. This review will help scientists, fellow researchers, and students to understand the applications of CE techniques in the impurity profiling of drugs.
Capillary electrophoresis (CE) is widely used for the impurity profiling of drugs that contain stereochemical centers in their structures, analysis of biomolecules, and characterization of biopharmaceuticals. Currently, CE is the method of choice for the analysis of foodstuffs and the determination of adulterants. This article discusses the general theory and instrumentation of CE as well as the classification of various CE techniques. It also presents an overview of research on the applications of different CE techniques in the impurity profiling of drugs in the past decade. The review briefly presents a comparison between CE and liquid chromatography methods and highlights the strengths of CE using drug compounds as examples. This review will help scientists, fellow researchers, and students to understand the applications of CE techniques in the impurity profiling of drugs.
2022, 12(3): 460-469.
doi: 10.1016/j.jpha.2021.09.013
摘要：
GuiLingJi (GLJ), a classic traditional Chinese medicine (TCM) formula, is composed of over 20 herbs, according to the Pharmacopeia of the People's Republic of China. Owing to its various activities, GLJ has been used in clinical settings for more than 400 years in China. However, the ambiguous chemical material basis limits the development of studies on the quality control and pharmacological mechanisms of GLJ. Therefore, comprehensive characterization of the multiple chemical components of GLJ is of great significance for the modernization of this formula. Given the great variety of herbs in GLJ, both UHPLC-MS and 1H NMR techniques were employed in this study. In addition, solvent extraction with different polarities was used to eliminate signal interference and the concentration of trace components. A variety of MS analytic methods were also used, including implementation of a self-built compound database, diagnostic ion filtering, mass defect filtering, and Compound Discoverer 3.0 analysis software. Based on the above strategies, a total of 150 compounds were identified, including 5 amino acids, 13 phenolic acids and glycosides, 11 coumarins, 72 flavones, 20 triterpenoid and triterpenoid saponins, 23 fatty acids, and 6 other compounds. Moreover, 13 compounds were identified by 1H NMR spectroscopy. The UHPLC-MS and 1H NMR results supported and complemented each other. This strategy provides a rapid approach to analyzing and identifying the chemical composition of Chinese herbal prescriptions. The current study provides basis for further research on the quality control and pharmacological mechanism of GLJ.
GuiLingJi (GLJ), a classic traditional Chinese medicine (TCM) formula, is composed of over 20 herbs, according to the Pharmacopeia of the People's Republic of China. Owing to its various activities, GLJ has been used in clinical settings for more than 400 years in China. However, the ambiguous chemical material basis limits the development of studies on the quality control and pharmacological mechanisms of GLJ. Therefore, comprehensive characterization of the multiple chemical components of GLJ is of great significance for the modernization of this formula. Given the great variety of herbs in GLJ, both UHPLC-MS and 1H NMR techniques were employed in this study. In addition, solvent extraction with different polarities was used to eliminate signal interference and the concentration of trace components. A variety of MS analytic methods were also used, including implementation of a self-built compound database, diagnostic ion filtering, mass defect filtering, and Compound Discoverer 3.0 analysis software. Based on the above strategies, a total of 150 compounds were identified, including 5 amino acids, 13 phenolic acids and glycosides, 11 coumarins, 72 flavones, 20 triterpenoid and triterpenoid saponins, 23 fatty acids, and 6 other compounds. Moreover, 13 compounds were identified by 1H NMR spectroscopy. The UHPLC-MS and 1H NMR results supported and complemented each other. This strategy provides a rapid approach to analyzing and identifying the chemical composition of Chinese herbal prescriptions. The current study provides basis for further research on the quality control and pharmacological mechanism of GLJ.
2022, 12(3): 500-508.
doi: 10.1016/j.jpha.2021.11.006
摘要：
Elucidating the active components of traditional Chinese medicine (TCM) is essential for understanding the mechanisms of TCM and promote its rational use as well as TCM-derived drug development. Recent studies have shown that surface plasmon resonance (SPR) technology is promising in this field. In the present study, we propose an SPR-based integrated strategy to screen and analyze the major active components of TCM. We used Radix Paeoniae Alba (RPA) as an example to identify the compounds that can account for its anti-inflammatory mechanism via tumor necrosis factor receptor type 1 (TNF-R1). First, RPA extraction was analyzed using an SPR-based screening system, and the potential active ingredients were collected, enriched, and identified as paeoniflorin and paeonol. Next, the affinity constants of paeoniflorin and paeonol were determined as 4.9 and 11.8 μM, respectively. Then, SPR-based competition assays and molecular docking were performed to show that the two compounds could compete with tumor necrosis factor-α (TNF-α) while binding to the subdomain 1 site of TNF-R1. Finally, in biological assays, the two compounds suppressed cytotoxicity and apoptosis induced by TNF-α in the L929 cell line. These findings prove that SPR technology is a useful tool for determining the active ingredients of TCM at the molecular level and can be used in various aspects of drug development. The SPR-based integrated strategy is reliable and feasible in TCM studies and will shed light on the elucidation of the pharmacological mechanism of TCM and facilitate its modernization.
Elucidating the active components of traditional Chinese medicine (TCM) is essential for understanding the mechanisms of TCM and promote its rational use as well as TCM-derived drug development. Recent studies have shown that surface plasmon resonance (SPR) technology is promising in this field. In the present study, we propose an SPR-based integrated strategy to screen and analyze the major active components of TCM. We used Radix Paeoniae Alba (RPA) as an example to identify the compounds that can account for its anti-inflammatory mechanism via tumor necrosis factor receptor type 1 (TNF-R1). First, RPA extraction was analyzed using an SPR-based screening system, and the potential active ingredients were collected, enriched, and identified as paeoniflorin and paeonol. Next, the affinity constants of paeoniflorin and paeonol were determined as 4.9 and 11.8 μM, respectively. Then, SPR-based competition assays and molecular docking were performed to show that the two compounds could compete with tumor necrosis factor-α (TNF-α) while binding to the subdomain 1 site of TNF-R1. Finally, in biological assays, the two compounds suppressed cytotoxicity and apoptosis induced by TNF-α in the L929 cell line. These findings prove that SPR technology is a useful tool for determining the active ingredients of TCM at the molecular level and can be used in various aspects of drug development. The SPR-based integrated strategy is reliable and feasible in TCM studies and will shed light on the elucidation of the pharmacological mechanism of TCM and facilitate its modernization.
2022, 12(3): 509-516.
doi: 10.1016/j.jpha.2021.12.004
摘要：
Homochiral metal-organic frameworks (MOFs) have attracted considerable attention in many fields of research, such as chiral catalysis and chiral chromatography. However, only few homochiral MOFs can be effectively used in capillary electrochromatography (CEC) and their performances are far from adequate. In this study, we successfully synthesized achiral nanocrystalline MIL-53. A facile post-synthetic modification strategy was then implemented to functionalize the product, yielding a homochiral MOF:l-His-NH-MIL-53. This MOF was then employed as a chiral coating in open-tubular CEC mode (OT-CEC), and, as such, it exhibited high enantioselectivities for several racemic drugs. The homochiral MOF and the fabricated capillary coating were systematically characterized using transmission electron microscopy, scanning electron microscopy (with energy-dispersive X-ray spectrometry), Fourier-transform infrared spectroscopy, X-ray diffractometry, thermogravimetric analysis, circular dichroism spectroscopy, Brunauer-Emmett-Teller surface area measurements, and X-ray photoelectron spectroscopy. This study is expected to provide a new strategy for the design and establishment of MOF-based chiral OT-CEC systems.
Homochiral metal-organic frameworks (MOFs) have attracted considerable attention in many fields of research, such as chiral catalysis and chiral chromatography. However, only few homochiral MOFs can be effectively used in capillary electrochromatography (CEC) and their performances are far from adequate. In this study, we successfully synthesized achiral nanocrystalline MIL-53. A facile post-synthetic modification strategy was then implemented to functionalize the product, yielding a homochiral MOF:l-His-NH-MIL-53. This MOF was then employed as a chiral coating in open-tubular CEC mode (OT-CEC), and, as such, it exhibited high enantioselectivities for several racemic drugs. The homochiral MOF and the fabricated capillary coating were systematically characterized using transmission electron microscopy, scanning electron microscopy (with energy-dispersive X-ray spectrometry), Fourier-transform infrared spectroscopy, X-ray diffractometry, thermogravimetric analysis, circular dichroism spectroscopy, Brunauer-Emmett-Teller surface area measurements, and X-ray photoelectron spectroscopy. This study is expected to provide a new strategy for the design and establishment of MOF-based chiral OT-CEC systems.
2023, 13(6): 545-562.
doi: 10.1016/j.jpha.2023.05.009
摘要：
As a ligand-dependent transcription factor, retinoid-associated orphan receptor γt (RORγt) that controls T helper (Th) 17 cell differentiation and interleukin (IL)-17 expression plays a critical role in the progression of several inflammatory and autoimmune conditions. An emerging novel approach to the therapy of these diseases thus involves controlling the transcriptional capacity of RORγt to decrease Th17 cell development and IL-17 production. Several RORγt inhibitors including both antagonists and inverse agonists have been discovered to regulate the transcriptional activity of RORγt by binding to orthosteric- or allosteric-binding sites in the ligand-binding domain. Some of small-molecule inhibitors have entered clinical evaluations. Therefore, in current review, the role of RORγt in Th17 regulation and Th17-related inflammatory and autoimmune diseases was highlighted. Notably, the recently developed RORγt inhibitors were summarized, with an emphasis on their optimization from lead compounds, efficacy, toxicity, mechanisms of action, and clinical trials. The limitations of current development in this area were also discussed to facilitate future research.
As a ligand-dependent transcription factor, retinoid-associated orphan receptor γt (RORγt) that controls T helper (Th) 17 cell differentiation and interleukin (IL)-17 expression plays a critical role in the progression of several inflammatory and autoimmune conditions. An emerging novel approach to the therapy of these diseases thus involves controlling the transcriptional capacity of RORγt to decrease Th17 cell development and IL-17 production. Several RORγt inhibitors including both antagonists and inverse agonists have been discovered to regulate the transcriptional activity of RORγt by binding to orthosteric- or allosteric-binding sites in the ligand-binding domain. Some of small-molecule inhibitors have entered clinical evaluations. Therefore, in current review, the role of RORγt in Th17 regulation and Th17-related inflammatory and autoimmune diseases was highlighted. Notably, the recently developed RORγt inhibitors were summarized, with an emphasis on their optimization from lead compounds, efficacy, toxicity, mechanisms of action, and clinical trials. The limitations of current development in this area were also discussed to facilitate future research.
2023, 13(7): 726-744.
doi: 10.1016/j.jpha.2023.04.013
摘要：
Colorectal tumors often create an immunosuppressive microenvironment that prevents them from responding to immunotherapy. Cannabidiol (CBD) is a non-psychoactive natural active ingredient from the cannabis plant that has various pharmacological effects, including neuroprotective, antiemetic, anti-inflammatory, and antineoplastic activities. This study aimed to elucidate the specific anticancer mechanism of CBD by single-cell RNA sequencing (scRNA-seq) and single-cell ATAC sequencing (scATAC-seq) technologies. Here, we report that CBD inhibits colorectal cancer progression by modulating the suppressive tumor microenvironment (TME). Our single-cell transcriptome and ATAC sequencing results showed that CBD suppressed M2-like macrophages and promoted M1-like macrophages in tumors both in strength and quantity. Furthermore, CBD significantly enhanced the interaction between M1-like macrophages and tumor cells and restored the intrinsic anti-tumor properties of macrophages, thereby preventing tumor progression. Mechanistically, CBD altered the metabolic pattern of macrophages and related anti-tumor signaling pathways. We found that CBD inhibited the alternative activation of macrophages and shifted the metabolic process from oxidative phosphorylation and fatty acid oxidation to glycolysis by inhibiting the phosphatidylinositol 3-kinase-protein kinase B signaling pathway and related downstream target genes. Furthermore, CBD-mediated macrophage plasticity enhanced the response to anti-programmed cell death protein-1 (PD-1) immunotherapy in xenografted mice. Taken together, we provide new insights into the anti-tumor effects of CBD.
Colorectal tumors often create an immunosuppressive microenvironment that prevents them from responding to immunotherapy. Cannabidiol (CBD) is a non-psychoactive natural active ingredient from the cannabis plant that has various pharmacological effects, including neuroprotective, antiemetic, anti-inflammatory, and antineoplastic activities. This study aimed to elucidate the specific anticancer mechanism of CBD by single-cell RNA sequencing (scRNA-seq) and single-cell ATAC sequencing (scATAC-seq) technologies. Here, we report that CBD inhibits colorectal cancer progression by modulating the suppressive tumor microenvironment (TME). Our single-cell transcriptome and ATAC sequencing results showed that CBD suppressed M2-like macrophages and promoted M1-like macrophages in tumors both in strength and quantity. Furthermore, CBD significantly enhanced the interaction between M1-like macrophages and tumor cells and restored the intrinsic anti-tumor properties of macrophages, thereby preventing tumor progression. Mechanistically, CBD altered the metabolic pattern of macrophages and related anti-tumor signaling pathways. We found that CBD inhibited the alternative activation of macrophages and shifted the metabolic process from oxidative phosphorylation and fatty acid oxidation to glycolysis by inhibiting the phosphatidylinositol 3-kinase-protein kinase B signaling pathway and related downstream target genes. Furthermore, CBD-mediated macrophage plasticity enhanced the response to anti-programmed cell death protein-1 (PD-1) immunotherapy in xenografted mice. Taken together, we provide new insights into the anti-tumor effects of CBD.
2022, 12(5): 719-724.
doi: 10.1016/j.jpha.2021.09.011
摘要：
Salvia miltiorrhiza Bge (SMB) has long been used in traditional Chinese medicine to treat cardiovascular and cerebrovascular diseases. Growing clinical usage has led to a huge demand for artificial planting of SMB. Thus, continuous cropping of SMB is an important challenge that needs to be addressed. Continuous cropping can alter the metabolic profile of plants, resulting in poor growth and low yield. In this study, we tried to image the spatial location and variation of endogenous metabolites in continuously cropped SMB using matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI). Spatially resolved expressions of tanshinones, salvianolic acids, polyamines, phenolic acids, amino acids, and oligosaccharides in normal and continuously cropped SMB roots were compared. The expressions of dihydrotanshinone I, tanshinone II A, dehydromiltirone, miltirone, dehydrotanshinone IIA, spermine, salvianolic acid B/E, tetrasaccharide, and pentasaccharide in continuously cropped SMB roots were much lower than those in normal roots. There was little difference in the expressions of caffeic acid and salvianolic acid A in normal and continuously cropped SMB roots. Ferulic acid was more widely distributed in xylem of normal SMB but strongly expressed in xylem, phloem, and cambium of continuously cropped SMB. The spatially resolved metabolite information enhances our understanding of the metabolic signature of continuously cropped SMB and also provides insights into the metabolic effects of continuous cropping in other plants.
Salvia miltiorrhiza Bge (SMB) has long been used in traditional Chinese medicine to treat cardiovascular and cerebrovascular diseases. Growing clinical usage has led to a huge demand for artificial planting of SMB. Thus, continuous cropping of SMB is an important challenge that needs to be addressed. Continuous cropping can alter the metabolic profile of plants, resulting in poor growth and low yield. In this study, we tried to image the spatial location and variation of endogenous metabolites in continuously cropped SMB using matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI). Spatially resolved expressions of tanshinones, salvianolic acids, polyamines, phenolic acids, amino acids, and oligosaccharides in normal and continuously cropped SMB roots were compared. The expressions of dihydrotanshinone I, tanshinone II A, dehydromiltirone, miltirone, dehydrotanshinone IIA, spermine, salvianolic acid B/E, tetrasaccharide, and pentasaccharide in continuously cropped SMB roots were much lower than those in normal roots. There was little difference in the expressions of caffeic acid and salvianolic acid A in normal and continuously cropped SMB roots. Ferulic acid was more widely distributed in xylem of normal SMB but strongly expressed in xylem, phloem, and cambium of continuously cropped SMB. The spatially resolved metabolite information enhances our understanding of the metabolic signature of continuously cropped SMB and also provides insights into the metabolic effects of continuous cropping in other plants.
2022, 12(6): 913-922.
doi: 10.1016/j.jpha.2022.07.001
摘要：
In this study, a fluorescent (FL) aptasensor was developed for on-site detection of live Salmonella typhimurium (S.T.) and Vibrio parahaemolyticus (V.P.). Complementary DNA (cDNA) of aptamer (Apt)-functionalized multicolor polyhedral oligomeric silsesquioxane-perovskite quantum dots (cDNA-POSS-PQDs) were used as encoded probes and combined with dual-stirring-bar-assisted signal amplification for pathogen quantification. In this system, bar 1 was labeled with the S.T. and V.P. Apts, and then bar 2 was functionalized with cDNA-POSS-PQDs. When S.T. and V.P. were introduced, pathogen-Apt complexes would form and be released into the supernatant from bar 1. Under agitation, the two complexes reached bar 2 and subsequently reacted with cDNA-POSS-PQDs, which were immobilized on MXene. Then, the encoded probes would be detached from bar 2 to generate FL signals in the supernatant. Notably, the pathogens can resume their free state and initiate next cycle. They swim between the two bars, and the FL signals can be gradually enhanced to maximum after several cycles. The FL signals from released encoded probes can be used to detect the analytes. In particular, live pathogens can be distinguished from dead ones by using an assay. The detection limits and linear range for S.T. and V.P. were 30 and 10 CFU/mL and 102–106 CFU/mL, respectively. Therefore, this assay has broad application potential for simultaneous on-site detection of various live pathogenic bacteria in water.
In this study, a fluorescent (FL) aptasensor was developed for on-site detection of live Salmonella typhimurium (S.T.) and Vibrio parahaemolyticus (V.P.). Complementary DNA (cDNA) of aptamer (Apt)-functionalized multicolor polyhedral oligomeric silsesquioxane-perovskite quantum dots (cDNA-POSS-PQDs) were used as encoded probes and combined with dual-stirring-bar-assisted signal amplification for pathogen quantification. In this system, bar 1 was labeled with the S.T. and V.P. Apts, and then bar 2 was functionalized with cDNA-POSS-PQDs. When S.T. and V.P. were introduced, pathogen-Apt complexes would form and be released into the supernatant from bar 1. Under agitation, the two complexes reached bar 2 and subsequently reacted with cDNA-POSS-PQDs, which were immobilized on MXene. Then, the encoded probes would be detached from bar 2 to generate FL signals in the supernatant. Notably, the pathogens can resume their free state and initiate next cycle. They swim between the two bars, and the FL signals can be gradually enhanced to maximum after several cycles. The FL signals from released encoded probes can be used to detect the analytes. In particular, live pathogens can be distinguished from dead ones by using an assay. The detection limits and linear range for S.T. and V.P. were 30 and 10 CFU/mL and 102–106 CFU/mL, respectively. Therefore, this assay has broad application potential for simultaneous on-site detection of various live pathogenic bacteria in water.
2023, 13(6): 616-624.
doi: 10.1016/j.jpha.2023.04.012
摘要：
Glioblastoma (GBM) is a lethal cancer with limited therapeutic options. Dendritic cell (DC)-based cancer vaccines provide a promising approach for GBM treatment. Clinical studies suggest that other immunotherapeutic agents may be combined with DC vaccines to further enhance antitumor activity. Here, we report a GBM case with combination immunotherapy consisting of DC vaccines, anti-programmed death-1 (anti-PD-1) and poly I:C as well as the chemotherapeutic agent cyclophosphamide that was integrated with standard chemoradiation therapy, and the patient remained disease-free for 69 months. The patient received DC vaccines loaded with multiple forms of tumor antigens, including mRNA-tumor associated antigens (TAA), mRNA-neoantigens, and hypochlorous acid (HOCl)-oxidized tumor lysates. Furthermore, mRNA-TAAs were modified with a novel TriVac technology that fuses TAAs with a destabilization domain and inserts TAAs into full-length lysosomal associated membrane protein-1 to enhance major histocompatibility complex (MHC) class I and II antigen presentation. The treatment consisted of 42 DC cancer vaccine infusions, 26 anti-PD-1 antibody nivolumab administrations and 126 poly I:C injections for DC infusions. The patient also received 28 doses of cyclophosphamide for depletion of regulatory T cells. No immunotherapy-related adverse events were observed during the treatment. Robust antitumor CD4+ and CD8+ T-cell responses were detected. The patient remains free of disease progression. This is the first case report on the combination of the above three agents to treat glioblastoma patients. Our results suggest that integrated combination immunotherapy is safe and feasible for long-term treatment in this patient. A large-scale trial to validate these findings is warranted.
Glioblastoma (GBM) is a lethal cancer with limited therapeutic options. Dendritic cell (DC)-based cancer vaccines provide a promising approach for GBM treatment. Clinical studies suggest that other immunotherapeutic agents may be combined with DC vaccines to further enhance antitumor activity. Here, we report a GBM case with combination immunotherapy consisting of DC vaccines, anti-programmed death-1 (anti-PD-1) and poly I:C as well as the chemotherapeutic agent cyclophosphamide that was integrated with standard chemoradiation therapy, and the patient remained disease-free for 69 months. The patient received DC vaccines loaded with multiple forms of tumor antigens, including mRNA-tumor associated antigens (TAA), mRNA-neoantigens, and hypochlorous acid (HOCl)-oxidized tumor lysates. Furthermore, mRNA-TAAs were modified with a novel TriVac technology that fuses TAAs with a destabilization domain and inserts TAAs into full-length lysosomal associated membrane protein-1 to enhance major histocompatibility complex (MHC) class I and II antigen presentation. The treatment consisted of 42 DC cancer vaccine infusions, 26 anti-PD-1 antibody nivolumab administrations and 126 poly I:C injections for DC infusions. The patient also received 28 doses of cyclophosphamide for depletion of regulatory T cells. No immunotherapy-related adverse events were observed during the treatment. Robust antitumor CD4+ and CD8+ T-cell responses were detected. The patient remains free of disease progression. This is the first case report on the combination of the above three agents to treat glioblastoma patients. Our results suggest that integrated combination immunotherapy is safe and feasible for long-term treatment in this patient. A large-scale trial to validate these findings is warranted.
2022, 12(6): 889-900.
doi: 10.1016/j.jpha.2022.08.004
摘要：
Bladder cancer (BC) is one of the most frequently diagnosed types of urinary cancer. Despite advances in treatment methods, no specific biomarkers are currently in use. Targeted and untargeted profiling of metabolites and elements of human blood serum from 100 BC patients and the same number of normal controls (NCs), with external validation, was attempted using three analytical methods, i.e., nuclear magnetic resonance, gold and silver-109 nanoparticle-based laser desorption/ionization mass spectrometry (LDI-MS), and inductively coupled plasma optical emission spectrometry (ICP-OES). All results were subjected to multivariate statistical analysis. Four potential serum biomarkers of BC, namely, isobutyrate, pyroglutamate, choline, and acetate, were quantified with proton nuclear magnetic resonance, which had excellent predictive ability as judged by the area under the curve (AUC) value of 0.999. Two elements, Li and Fe, were also found to distinguish between cancer and control samples, as judged from ICP-OES data and AUC of 0.807 (in validation set). Twenty-five putatively identified compounds, mostly related to glycans and lipids, differentiated BC from NCs, as detected using LDI-MS. Five serum metabolites were found to discriminate between tumor grades and nine metabolites between tumor stages. The results from three different analytical platforms demonstrate that the identified distinct serum metabolites and metal elements have potential to be used for noninvasive detection, staging, and grading of BC.
Bladder cancer (BC) is one of the most frequently diagnosed types of urinary cancer. Despite advances in treatment methods, no specific biomarkers are currently in use. Targeted and untargeted profiling of metabolites and elements of human blood serum from 100 BC patients and the same number of normal controls (NCs), with external validation, was attempted using three analytical methods, i.e., nuclear magnetic resonance, gold and silver-109 nanoparticle-based laser desorption/ionization mass spectrometry (LDI-MS), and inductively coupled plasma optical emission spectrometry (ICP-OES). All results were subjected to multivariate statistical analysis. Four potential serum biomarkers of BC, namely, isobutyrate, pyroglutamate, choline, and acetate, were quantified with proton nuclear magnetic resonance, which had excellent predictive ability as judged by the area under the curve (AUC) value of 0.999. Two elements, Li and Fe, were also found to distinguish between cancer and control samples, as judged from ICP-OES data and AUC of 0.807 (in validation set). Twenty-five putatively identified compounds, mostly related to glycans and lipids, differentiated BC from NCs, as detected using LDI-MS. Five serum metabolites were found to discriminate between tumor grades and nine metabolites between tumor stages. The results from three different analytical platforms demonstrate that the identified distinct serum metabolites and metal elements have potential to be used for noninvasive detection, staging, and grading of BC.
2022, 12(3): 453-459.
doi: 10.1016/j.jpha.2021.09.007
摘要：
Rutin, a flavonoid found in fruits and vegetables, is a potential anticancer compound with strong anticancer activity. Therefore, electrochemical sensor was developed for the detection of rutin. In this study, CoWO4 nanosheets were synthesized via a hydrothermal method, and porous carbon (PC) was prepared via high-temperature pyrolysis. Successful preparation of the materials was confirmed, and characterization was performed by transmission electron microscopy, scanning electron microscopy, and X-ray photoelectron spectroscopy. A mixture of PC and CoWO4 nanosheets was used as an electrode modifier to fabricate the electrochemical sensor for the electrochemical determination of rutin. The 3D CoWO4 nanosheets exhibited high electrocatalytic activity and good stability. PC has a high surface-to-volume ratio and superior conductivity. Moreover, the hydrophobicity of PC allows large amounts of rutin to be adsorbed, thereby increasing the concentration of rutin at the electrode surface. Owing to the synergistic effect of the 3D CoWO4 nanosheets and PC, the developed electrochemical sensor was employed to quantitively determine rutin with high stability and sensitivity. The sensor showed a good linear range (5-5000 ng/mL) with a detection limit of 0.45 ng/mL. The developed sensor was successfully applied to the determination of rutin in crushed tablets and human serum samples.
Rutin, a flavonoid found in fruits and vegetables, is a potential anticancer compound with strong anticancer activity. Therefore, electrochemical sensor was developed for the detection of rutin. In this study, CoWO4 nanosheets were synthesized via a hydrothermal method, and porous carbon (PC) was prepared via high-temperature pyrolysis. Successful preparation of the materials was confirmed, and characterization was performed by transmission electron microscopy, scanning electron microscopy, and X-ray photoelectron spectroscopy. A mixture of PC and CoWO4 nanosheets was used as an electrode modifier to fabricate the electrochemical sensor for the electrochemical determination of rutin. The 3D CoWO4 nanosheets exhibited high electrocatalytic activity and good stability. PC has a high surface-to-volume ratio and superior conductivity. Moreover, the hydrophobicity of PC allows large amounts of rutin to be adsorbed, thereby increasing the concentration of rutin at the electrode surface. Owing to the synergistic effect of the 3D CoWO4 nanosheets and PC, the developed electrochemical sensor was employed to quantitively determine rutin with high stability and sensitivity. The sensor showed a good linear range (5-5000 ng/mL) with a detection limit of 0.45 ng/mL. The developed sensor was successfully applied to the determination of rutin in crushed tablets and human serum samples.
2022, 12(4): 610-616.
doi: 10.1016/j.jpha.2022.06.005
摘要：
Covalent organic frameworks (COFs) are a novel type of crystalline porous organic polymer materials recently developed. It has several advantages in chromatographic separation field, such as high thermal stability, porosity, structural regularity, and large specific surface area. Here, a novel spherical COF 1,3,5-tris(4-aminophenyl)benzene (TAPB) and 2,5-bis(2-propyn-1-yloxy)-1,4-benzenedicarboxaldehyde (BPTA) was developed as an electrochromatographic stationary phase for capillary electrochromatography separation. The COF TAPB-BPTA modified capillary column was fabricated via a facile in situ growth method at room temperature. The characterization results of scanning electron microscopy (SEM), Fourier transform infrared (FT-IR) spectroscopy, and X-ray diffraction (XRD) confirmed that COF TAPB-BPTA were successfully modified onto the capillary inner surface. The electrochromatography separation performance of the COF TAPB-BPTA modified capillary was investigated. The prepared column demonstrated outstanding separation performance toward alkylbenzenes, phenols, and chlorobenzenes compounds. Furthermore, the baseline separations of non-steroidal anti-inflammatory drugs (NSAIDs) and parabens with good efficiency and high resolution were achieved. Also, the prepared column possessed satisfactory precision of the intra-day runs (n=5), inter-day runs (n=3), and parallel columns (n=3), and the relative standard deviations (RSDs) of the retention times of tested alkylbenzenes were all less than 2.58%. Thus, this new COF-based stationary phase shows tremendous application potential in chromatographic separation field.
Covalent organic frameworks (COFs) are a novel type of crystalline porous organic polymer materials recently developed. It has several advantages in chromatographic separation field, such as high thermal stability, porosity, structural regularity, and large specific surface area. Here, a novel spherical COF 1,3,5-tris(4-aminophenyl)benzene (TAPB) and 2,5-bis(2-propyn-1-yloxy)-1,4-benzenedicarboxaldehyde (BPTA) was developed as an electrochromatographic stationary phase for capillary electrochromatography separation. The COF TAPB-BPTA modified capillary column was fabricated via a facile in situ growth method at room temperature. The characterization results of scanning electron microscopy (SEM), Fourier transform infrared (FT-IR) spectroscopy, and X-ray diffraction (XRD) confirmed that COF TAPB-BPTA were successfully modified onto the capillary inner surface. The electrochromatography separation performance of the COF TAPB-BPTA modified capillary was investigated. The prepared column demonstrated outstanding separation performance toward alkylbenzenes, phenols, and chlorobenzenes compounds. Furthermore, the baseline separations of non-steroidal anti-inflammatory drugs (NSAIDs) and parabens with good efficiency and high resolution were achieved. Also, the prepared column possessed satisfactory precision of the intra-day runs (n=5), inter-day runs (n=3), and parallel columns (n=3), and the relative standard deviations (RSDs) of the retention times of tested alkylbenzenes were all less than 2.58%. Thus, this new COF-based stationary phase shows tremendous application potential in chromatographic separation field.
2023, 13(1): 99-109.
doi: 10.1016/j.jpha.2022.09.003
摘要：
Traditional microtubule inhibitors fail to significantly enhance the effect of colorectal cancer; hence, new and efficient strategies are necessary. In this study, a supramolecular nanoreactor (DOC@TA-Fe3+) based on tannic acid (TA), iron ion (Fe3+), and docetaxel (DOC) with microtubule inhibition, reactive oxygen species (ROS) generation, and glutathione peroxidase 4 (GPX4) inhibition, is prepared for ferroptosis/apoptosis treatment. After internalization by CT26 cells, the DOC@TA-Fe3+ nanoreactor escapes from the lysosomes to release payloads. The subsequent Fe3+/Fe2+ conversion mediated by TA reducibility can trigger the Fenton reaction to enhance the ROS concentration. Additionally, Fe3+ can consume glutathione to repress the activity of GPX4 to induce ferroptosis. Meanwhile, the released DOC controls microtubule dynamics to activate the apoptosis pathway. The superior in vivo antitumor efficacy of DOC@TA-Fe3+ nanoreactor in terms of tumor growth inhibition and improved survival is verified in CT26 tumor-bearing mouse model. Therefore, the nanoreactor can act as an effective apoptosis and ferroptosis inducer for application in colorectal cancer therapy.
Traditional microtubule inhibitors fail to significantly enhance the effect of colorectal cancer; hence, new and efficient strategies are necessary. In this study, a supramolecular nanoreactor (DOC@TA-Fe3+) based on tannic acid (TA), iron ion (Fe3+), and docetaxel (DOC) with microtubule inhibition, reactive oxygen species (ROS) generation, and glutathione peroxidase 4 (GPX4) inhibition, is prepared for ferroptosis/apoptosis treatment. After internalization by CT26 cells, the DOC@TA-Fe3+ nanoreactor escapes from the lysosomes to release payloads. The subsequent Fe3+/Fe2+ conversion mediated by TA reducibility can trigger the Fenton reaction to enhance the ROS concentration. Additionally, Fe3+ can consume glutathione to repress the activity of GPX4 to induce ferroptosis. Meanwhile, the released DOC controls microtubule dynamics to activate the apoptosis pathway. The superior in vivo antitumor efficacy of DOC@TA-Fe3+ nanoreactor in terms of tumor growth inhibition and improved survival is verified in CT26 tumor-bearing mouse model. Therefore, the nanoreactor can act as an effective apoptosis and ferroptosis inducer for application in colorectal cancer therapy.
2023, 13(4): 367-375.
doi: 10.1016/j.jpha.2023.02.011
摘要：
Claudin18.2 (CLDN18.2) is a tight junction protein that is overexpressed in a variety of solid tumors such as gastrointestinal cancer and oesophageal cancer. It has been identified as a promising target and a potential biomarker to diagnose tumor, evaluate efficacy, and determine patient prognosis. TST001 is a recombinant humanized CLDN18.2 antibody that selectively binds to the extracellular loop of human Claudin18.2. In this study, we constructed a solid target radionuclide zirconium-89 (89Zr) labled-TST001 to detect the expression of in the human stomach cancer BGC823CLDN18.2 cell lines. The [89Zr]Zr-desferrioxamine (DFO)-TST001 showed high radiochemical purity (RCP, >99%) and specific activity (24.15±1.34 GBq/μmol), and was stable in 5% human serum albumin, and phosphate buffer saline (>85% RCP at 96h). The EC50 values of TST001 and DFO-TST001 were as high as 0.413±0.055 and 0.361±0.058nM(P>0.05), respectively. The radiotracer had a significantly higher average standard uptake values in CLDN18.2-positive tumors than in CLDN18.2-negative tumors (1.11±0.02 vs. 0.49±0.03, P=0.0016) 2 days post injection (p.i.). BGC823CLDN18.2 mice models showed high tumor/muscle ratios 96h p.i. with [89Zr]Zr-DFO-TST001 was much higher than those of the other imaging groups. Immunohistochemistry results showed that BGC823CLDN18.2 tumors were highly positive (+++) for CLDN18.2, while those in the BGC823 group did not express CLDN18.2 (-). The results of exvivo biodistribution studies showed that there was a higher distribution in the BGC823CLDN18.2 tumor bearing mice (2.05±0.16 %ID/g) than BGC823 mice (0.69±0.02 %ID/g) and blocking group (0.72±0.02 %ID/g). A dosimetry estimation study showed that the effective dose of [89Zr]Zr-DFO-TST001 was 0.0705 mSv/MBq, which is within the range of acceptable doses for nuclear medicine research. Taken together, these results suggest that Good Manufacturing Practices produced by this immuno-positron emission tomography probe can detect CLDN18.2-overexpressing tumors.
Claudin18.2 (CLDN18.2) is a tight junction protein that is overexpressed in a variety of solid tumors such as gastrointestinal cancer and oesophageal cancer. It has been identified as a promising target and a potential biomarker to diagnose tumor, evaluate efficacy, and determine patient prognosis. TST001 is a recombinant humanized CLDN18.2 antibody that selectively binds to the extracellular loop of human Claudin18.2. In this study, we constructed a solid target radionuclide zirconium-89 (89Zr) labled-TST001 to detect the expression of in the human stomach cancer BGC823CLDN18.2 cell lines. The [89Zr]Zr-desferrioxamine (DFO)-TST001 showed high radiochemical purity (RCP, >99%) and specific activity (24.15±1.34 GBq/μmol), and was stable in 5% human serum albumin, and phosphate buffer saline (>85% RCP at 96h). The EC50 values of TST001 and DFO-TST001 were as high as 0.413±0.055 and 0.361±0.058nM(P>0.05), respectively. The radiotracer had a significantly higher average standard uptake values in CLDN18.2-positive tumors than in CLDN18.2-negative tumors (1.11±0.02 vs. 0.49±0.03, P=0.0016) 2 days post injection (p.i.). BGC823CLDN18.2 mice models showed high tumor/muscle ratios 96h p.i. with [89Zr]Zr-DFO-TST001 was much higher than those of the other imaging groups. Immunohistochemistry results showed that BGC823CLDN18.2 tumors were highly positive (+++) for CLDN18.2, while those in the BGC823 group did not express CLDN18.2 (-). The results of exvivo biodistribution studies showed that there was a higher distribution in the BGC823CLDN18.2 tumor bearing mice (2.05±0.16 %ID/g) than BGC823 mice (0.69±0.02 %ID/g) and blocking group (0.72±0.02 %ID/g). A dosimetry estimation study showed that the effective dose of [89Zr]Zr-DFO-TST001 was 0.0705 mSv/MBq, which is within the range of acceptable doses for nuclear medicine research. Taken together, these results suggest that Good Manufacturing Practices produced by this immuno-positron emission tomography probe can detect CLDN18.2-overexpressing tumors.
2023, 13(6): 625-639.
doi: 10.1016/j.jpha.2023.04.009
摘要：
In non-small cell lung cancer (NSCLC), the heterogeneity promotes drug resistance, and the restricted expression of programmed death-ligand 1 (PD-L1) limits the immunotherapy benefits. Based on the mechanisms related to translation regulation and the association with PD-L1 of methyltransferase-like 3 (METTL3), the novel small-molecule inhibitor STM2457 is assumed to be useful for the treatment of NSCLC. We evaluated the efficacy of STM2457 in vivo and in vitro and confirmed the effects of its inhibition on disease progression. Next, we explored the effect of STM2457 on METTL3 and revealed its effects on the inhibition of catalytic activity and upregulation of METTL3 protein expression. Importantly, we described the genome-wide characteristics of multiple omics data acquired from RNA sequencing, ribosome profiling, and methylated RNA immunoprecipitation sequencing data under STM2457 treatment or METTL3 knockout. We also constructed a model for the regulation of the translation of METTL3 and PD-L1. Finally, we found PD-L1 upregulation by STM2457 in vivo and in vitro. In conclusion, STM2457 is a potential novel suppressor based on its inhibitory effect on tumor progression and may be able to overcome the heterogeneity based on its impact on the translatome. Furthermore, it can improve the immunotherapy outcomes based on PD-L1 upregulation in NSCLC.
In non-small cell lung cancer (NSCLC), the heterogeneity promotes drug resistance, and the restricted expression of programmed death-ligand 1 (PD-L1) limits the immunotherapy benefits. Based on the mechanisms related to translation regulation and the association with PD-L1 of methyltransferase-like 3 (METTL3), the novel small-molecule inhibitor STM2457 is assumed to be useful for the treatment of NSCLC. We evaluated the efficacy of STM2457 in vivo and in vitro and confirmed the effects of its inhibition on disease progression. Next, we explored the effect of STM2457 on METTL3 and revealed its effects on the inhibition of catalytic activity and upregulation of METTL3 protein expression. Importantly, we described the genome-wide characteristics of multiple omics data acquired from RNA sequencing, ribosome profiling, and methylated RNA immunoprecipitation sequencing data under STM2457 treatment or METTL3 knockout. We also constructed a model for the regulation of the translation of METTL3 and PD-L1. Finally, we found PD-L1 upregulation by STM2457 in vivo and in vitro. In conclusion, STM2457 is a potential novel suppressor based on its inhibitory effect on tumor progression and may be able to overcome the heterogeneity based on its impact on the translatome. Furthermore, it can improve the immunotherapy outcomes based on PD-L1 upregulation in NSCLC.
2022, 12(6): 839-851.
doi: 10.1016/j.jpha.2022.07.004
摘要：
Glycyrrhizae Radix et Rhizoma, a traditional Chinese medicine also known as Gan Cao (GC), is frequently included in clinical prescriptions for the treatment of pneumonia. However, the pharmacological components of GC for pneumonia treatment are rarely explored. Gan An He Ji oral liquid (GAHJ) has a simple composition and contains GC liquid extracts and paregoric, and has been used clinically for many years. Therefore, GAHJ was selected as a compound preparation for the study of GC in the treatment of pneumonia. We conducted an in vivo study of patients with pneumonia undergoing GAHJ treatments for three days. Using the intelligent mass spectrometry data-processing technologies to analyze the metabolism of GC in vivo, we obtained 168 related components of GC in humans, consisting of 24 prototype components and 144 metabolites, with 135 compounds screened in plasma and 82 in urine. After analysis of the metabolic transformation relationship and relative exposure, six components (liquiritin, liquiritigenin, glycyrrhizin, glycyrrhetinic acid, daidzin, and formononetin) were selected as potential effective components. The experimental results based on two animal pneumonia models and the inflammatory cell model showed that the mixture of these six components was effective in the treatment of pneumonia and lung injury and could effectively downregulate the level of inducible nitric oxide synthase (iNOS). Interestingly, glycyrrhetinic acid exhibited the strongest inhibition on iNOS and the highest exposure in vivo. The following molecular dynamic simulations indicated a strong bond between glycyrrhetinic acid and iNOS. Thus, the current study provides a pharmaceutical basis for GC and reveals the possible corresponding mechanisms in pneumonia treatment.
Glycyrrhizae Radix et Rhizoma, a traditional Chinese medicine also known as Gan Cao (GC), is frequently included in clinical prescriptions for the treatment of pneumonia. However, the pharmacological components of GC for pneumonia treatment are rarely explored. Gan An He Ji oral liquid (GAHJ) has a simple composition and contains GC liquid extracts and paregoric, and has been used clinically for many years. Therefore, GAHJ was selected as a compound preparation for the study of GC in the treatment of pneumonia. We conducted an in vivo study of patients with pneumonia undergoing GAHJ treatments for three days. Using the intelligent mass spectrometry data-processing technologies to analyze the metabolism of GC in vivo, we obtained 168 related components of GC in humans, consisting of 24 prototype components and 144 metabolites, with 135 compounds screened in plasma and 82 in urine. After analysis of the metabolic transformation relationship and relative exposure, six components (liquiritin, liquiritigenin, glycyrrhizin, glycyrrhetinic acid, daidzin, and formononetin) were selected as potential effective components. The experimental results based on two animal pneumonia models and the inflammatory cell model showed that the mixture of these six components was effective in the treatment of pneumonia and lung injury and could effectively downregulate the level of inducible nitric oxide synthase (iNOS). Interestingly, glycyrrhetinic acid exhibited the strongest inhibition on iNOS and the highest exposure in vivo. The following molecular dynamic simulations indicated a strong bond between glycyrrhetinic acid and iNOS. Thus, the current study provides a pharmaceutical basis for GC and reveals the possible corresponding mechanisms in pneumonia treatment.
2022, 12(1): 113-121.
doi: 10.1016/j.jpha.2021.03.010
摘要：
Regulating the catalytic activity of nanozymes is significant for their applications in various fields. Here, we demonstrate a new strategy to achieve reversible regulation of the nanozyme's activity for sensing purpose. This strategy involves the use of zero-dimensional MoS2 quantum dots (MQDs) as the building blocks of nanozymes which display very weak peroxidase (POD)-like activity. Interestingly, such POD-like activity of the MQDs largely enhances in the presence of Fe3+ while diminishes with the addition of captopril thereafter. Further investigations identify the mechanism of Fe3+-mediated aggregation-induced enhancement of the POD-like activity and the inhibitory effect of captopril on the enhancement, which is highly dependent on their concentrations. Based on this finding, a colorimetric method for the detection of captopril is developed. This sensing approach exhibits the merits of simplicity, rapidness, reliability, and low cost, which has been successfully applied in quality control of captopril in pharmaceutical products. Moreover, the present sensing platform allows smartphone read-out, which has promising applications in point-of-care testing devices for clinical diagnosis and drug analysis.
Regulating the catalytic activity of nanozymes is significant for their applications in various fields. Here, we demonstrate a new strategy to achieve reversible regulation of the nanozyme's activity for sensing purpose. This strategy involves the use of zero-dimensional MoS2 quantum dots (MQDs) as the building blocks of nanozymes which display very weak peroxidase (POD)-like activity. Interestingly, such POD-like activity of the MQDs largely enhances in the presence of Fe3+ while diminishes with the addition of captopril thereafter. Further investigations identify the mechanism of Fe3+-mediated aggregation-induced enhancement of the POD-like activity and the inhibitory effect of captopril on the enhancement, which is highly dependent on their concentrations. Based on this finding, a colorimetric method for the detection of captopril is developed. This sensing approach exhibits the merits of simplicity, rapidness, reliability, and low cost, which has been successfully applied in quality control of captopril in pharmaceutical products. Moreover, the present sensing platform allows smartphone read-out, which has promising applications in point-of-care testing devices for clinical diagnosis and drug analysis.
2023, 13(3): 255-261.
doi: 10.1016/j.jpha.2022.10.005
摘要：
On December 22, 2021, the United States Food and Drug Administration approved the first main protease inhibitor, i.e., oral antiviral nirmatrelvir (PF-07321332)/ritonavir (Paxlovid), for the treatment of early severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Nirmatrelvir inhibits SARS-CoV-2 infection, but high doses or long-term treatment may cause embryonic developmental toxicity and changes in host gene expression. The chiral structure of nirmatrelvir plays a key role in its antiviral activity. Ritonavir boosts the efficacy of nirmatrelvir by inactivating cytochrome P450 3A4 expression and occupying the plasma protein binding sites. Multidrug resistance protein 1 inhibitors may increase the efficacy of nirmatrelvir. However, Paxlovid has many contraindications. Some patients treated with Paxlovid experience a second round of coronavirus disease 2019 (COVID-19) symptoms soon after recovery. Interestingly, the antiviral activity of nirmatrelvir metabolites, such as compounds 12–18 , is similar to or higher than that of nirmatrelvir. Herein, we review the advances and challenges in using nirmatrelvir and its derivatives with the aim of providing knowledge for drug developers and physicians in the fight against COVID-19.
On December 22, 2021, the United States Food and Drug Administration approved the first main protease inhibitor, i.e., oral antiviral nirmatrelvir (PF-07321332)/ritonavir (Paxlovid), for the treatment of early severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Nirmatrelvir inhibits SARS-CoV-2 infection, but high doses or long-term treatment may cause embryonic developmental toxicity and changes in host gene expression. The chiral structure of nirmatrelvir plays a key role in its antiviral activity. Ritonavir boosts the efficacy of nirmatrelvir by inactivating cytochrome P450 3A4 expression and occupying the plasma protein binding sites. Multidrug resistance protein 1 inhibitors may increase the efficacy of nirmatrelvir. However, Paxlovid has many contraindications. Some patients treated with Paxlovid experience a second round of coronavirus disease 2019 (COVID-19) symptoms soon after recovery. Interestingly, the antiviral activity of nirmatrelvir metabolites, such as compounds 12–18 , is similar to or higher than that of nirmatrelvir. Herein, we review the advances and challenges in using nirmatrelvir and its derivatives with the aim of providing knowledge for drug developers and physicians in the fight against COVID-19.
2022, 12(3): 380-393.
doi: 10.1016/j.jpha.2021.07.006
摘要：
Natural products provide a bountiful supply of pharmacologically relevant precursors for the development of various drug-related molecules, including radiopharmaceuticals. However, current knowledge regarding the importance of natural products in developing new radiopharmaceuticals remains limited. To date, several radionuclides, including gallium-68, technetium-99m, fluorine-18, iodine-131, and iodine-125, have been extensively studied for the synthesis of diagnostic and therapeutic radiopharmaceuticals. The availability of various radiolabeling methods allows the incorporation of these radionuclides into bioactive molecules in a practical and efficient manner. Of the radiolabeling methods, direct radioiodination, radiometal complexation, and halogenation are generally suitable for natural products owing to their simplicity and robustness. This review highlights the pharmacological benefits of curcumin and its analogs, flavonoids, and marine peptides in treating human pathologies and provides a perspective on the potential use of these bioactive compounds as molecular templates for the design and development of new radiopharmaceuticals. Additionally, this review provides insights into the current strategies for labeling natural products with various radionuclides using either direct or indirect methods.
Natural products provide a bountiful supply of pharmacologically relevant precursors for the development of various drug-related molecules, including radiopharmaceuticals. However, current knowledge regarding the importance of natural products in developing new radiopharmaceuticals remains limited. To date, several radionuclides, including gallium-68, technetium-99m, fluorine-18, iodine-131, and iodine-125, have been extensively studied for the synthesis of diagnostic and therapeutic radiopharmaceuticals. The availability of various radiolabeling methods allows the incorporation of these radionuclides into bioactive molecules in a practical and efficient manner. Of the radiolabeling methods, direct radioiodination, radiometal complexation, and halogenation are generally suitable for natural products owing to their simplicity and robustness. This review highlights the pharmacological benefits of curcumin and its analogs, flavonoids, and marine peptides in treating human pathologies and provides a perspective on the potential use of these bioactive compounds as molecular templates for the design and development of new radiopharmaceuticals. Additionally, this review provides insights into the current strategies for labeling natural products with various radionuclides using either direct or indirect methods.
2023, 13(4): 421-429.
doi: 10.1016/j.jpha.2023.03.003
摘要：
Chiral metal-organic frameworks (CMOFs) with enantiomeric subunits have been employed in chiral chemistry. In this study, a CMOF formed from 6-methoxyl-(8S,9R)-cinchonan-9-ol-3-carboxylic acid (HQA) and ZnCl2, {(HQA)(ZnCl2)(2.5H2O)}n, was constructed as a chiral stationary phase (CSP) via an in situ fabrication approach and used for chiral amino acid and drug analyses for the first time. The {(HQA)(ZnCl2)(2.5H2O)}n nanocrystal and the corresponding chiral stationary phase were systematically characterised using a series of analytical techniques including scanning electron microscopy, X-ray diffraction, Fourier transform infrared spectroscopy, circular dichroism, X-ray photoelectron spectroscopy, thermogravimetric analysis, and Brunauer-Emmett-Teller surface area measurements. In open-tubular capillary electrochromatography (CEC), the novel chiral column exhibited strong and broad enantioselectivity toward a variety of chiral analytes, including 19 racemic dansyl amino acids and several model chiral drugs (both acidic and basic). The chiral CEC conditions were optimised, and the enantioseparation mechanisms are discussed. This study not only introduces a new high-efficiency member of the MOF-type CSP family but also demonstrates the potential of improving the enantioselectivities of traditional chiral recognition reagents by fully using the inherent characteristics of porous organic frameworks.
Chiral metal-organic frameworks (CMOFs) with enantiomeric subunits have been employed in chiral chemistry. In this study, a CMOF formed from 6-methoxyl-(8S,9R)-cinchonan-9-ol-3-carboxylic acid (HQA) and ZnCl2, {(HQA)(ZnCl2)(2.5H2O)}n, was constructed as a chiral stationary phase (CSP) via an in situ fabrication approach and used for chiral amino acid and drug analyses for the first time. The {(HQA)(ZnCl2)(2.5H2O)}n nanocrystal and the corresponding chiral stationary phase were systematically characterised using a series of analytical techniques including scanning electron microscopy, X-ray diffraction, Fourier transform infrared spectroscopy, circular dichroism, X-ray photoelectron spectroscopy, thermogravimetric analysis, and Brunauer-Emmett-Teller surface area measurements. In open-tubular capillary electrochromatography (CEC), the novel chiral column exhibited strong and broad enantioselectivity toward a variety of chiral analytes, including 19 racemic dansyl amino acids and several model chiral drugs (both acidic and basic). The chiral CEC conditions were optimised, and the enantioseparation mechanisms are discussed. This study not only introduces a new high-efficiency member of the MOF-type CSP family but also demonstrates the potential of improving the enantioselectivities of traditional chiral recognition reagents by fully using the inherent characteristics of porous organic frameworks.
2023, 13(9): 968-983.
doi: 10.1016/j.jpha.2023.05.015
摘要：
Ischemic stroke (IS) is a multifactorial and heterogeneous disease. Despite years of studies, effective strategies for the diagnosis, management and treatment of stroke are still lacking in clinical practice. Metabolomics is a growing field in systems biology. It is starting to show promise in the identification of biomarkers and in the use of pharmacometabolomics to help patients with certain disorders choose their course of treatment. The development of metabolomics has enabled further and more biological applications. Particularly, metabolomics is increasingly being used to diagnose diseases, discover new drug targets, elucidate mechanisms, and monitor therapeutic outcomes and its potential effect on precision medicine. In this review, we reviewed some recent advances in the study of metabolomics as well as how metabolomics might be used to identify novel biomarkers and understand the mechanisms of IS. Then, the use of metabolomics approaches to investigate the molecular processes and active ingredients of Chinese herbal formulations with anti-IS capabilities is summarized. We finally summarized recent developments in single cell metabolomics for exploring the metabolic profiles of single cells. Although the field is relatively young, the development of single cell metabolomics promises to provide a powerful tool for unraveling the pathogenesis of IS.
Ischemic stroke (IS) is a multifactorial and heterogeneous disease. Despite years of studies, effective strategies for the diagnosis, management and treatment of stroke are still lacking in clinical practice. Metabolomics is a growing field in systems biology. It is starting to show promise in the identification of biomarkers and in the use of pharmacometabolomics to help patients with certain disorders choose their course of treatment. The development of metabolomics has enabled further and more biological applications. Particularly, metabolomics is increasingly being used to diagnose diseases, discover new drug targets, elucidate mechanisms, and monitor therapeutic outcomes and its potential effect on precision medicine. In this review, we reviewed some recent advances in the study of metabolomics as well as how metabolomics might be used to identify novel biomarkers and understand the mechanisms of IS. Then, the use of metabolomics approaches to investigate the molecular processes and active ingredients of Chinese herbal formulations with anti-IS capabilities is summarized. We finally summarized recent developments in single cell metabolomics for exploring the metabolic profiles of single cells. Although the field is relatively young, the development of single cell metabolomics promises to provide a powerful tool for unraveling the pathogenesis of IS.
2022, 12(4): 683-691.
doi: 10.1016/j.jpha.2022.04.002
摘要：
Although herbal medicines (HMs) are widely used in the prevention and treatment of obesity and obesity-associated disorders, the key constituents exhibiting anti-obesity activity and their molecular mechanisms are poorly understood. Recently, we assessed the inhibitory potentials of several HMs against human pancreatic lipase (hPL, a key therapeutic target for human obesity), among which the root-extract of Rhodiola crenulata (ERC) showed the most potent anti-hPL activity. In this study, we adopted an integrated strategy, involving bioactivity-guided fractionation techniques, chemical profiling, and biochemical assays, to identify the key anti-hPL constituents in ERC. Nine ERC fractions (retention time=12.5-35 min), obtained using reverse-phase liquid chromatography, showed strong anti-hPL activity, while the major constituents in these bioactive fractions were subsequently identified using liquid chromatography-quadrupole time-of-flight mass spectrometry (LC-Q-TOF-MS/MS). Among the identified ERC constituents, 1,2,3,4,6-penta-O-galloyl-β-d-glucopyranose (PGG) and catechin gallate (CG) showed the most potent anti-hPL activity, with pIC50 values of 7.59 ±0.03 and 7.68 ±0.23, respectively. Further investigations revealed that PGG and CG potently inhibited hPL in a non-competitive manner, with inhibition constant (Ki) values of 0.012 and 0.082 μM, respectively. Collectively, our integrative analyses enabled us to efficiently identify and characterize the key anti-obesity constituents in ERC, as well as to elucidate their anti-hPL mechanisms. These findings provide convincing evidence in support of the anti-obesity and lipid-lowering properties of ERC.
Although herbal medicines (HMs) are widely used in the prevention and treatment of obesity and obesity-associated disorders, the key constituents exhibiting anti-obesity activity and their molecular mechanisms are poorly understood. Recently, we assessed the inhibitory potentials of several HMs against human pancreatic lipase (hPL, a key therapeutic target for human obesity), among which the root-extract of Rhodiola crenulata (ERC) showed the most potent anti-hPL activity. In this study, we adopted an integrated strategy, involving bioactivity-guided fractionation techniques, chemical profiling, and biochemical assays, to identify the key anti-hPL constituents in ERC. Nine ERC fractions (retention time=12.5-35 min), obtained using reverse-phase liquid chromatography, showed strong anti-hPL activity, while the major constituents in these bioactive fractions were subsequently identified using liquid chromatography-quadrupole time-of-flight mass spectrometry (LC-Q-TOF-MS/MS). Among the identified ERC constituents, 1,2,3,4,6-penta-O-galloyl-β-d-glucopyranose (PGG) and catechin gallate (CG) showed the most potent anti-hPL activity, with pIC50 values of 7.59 ±0.03 and 7.68 ±0.23, respectively. Further investigations revealed that PGG and CG potently inhibited hPL in a non-competitive manner, with inhibition constant (Ki) values of 0.012 and 0.082 μM, respectively. Collectively, our integrative analyses enabled us to efficiently identify and characterize the key anti-obesity constituents in ERC, as well as to elucidate their anti-hPL mechanisms. These findings provide convincing evidence in support of the anti-obesity and lipid-lowering properties of ERC.
2023, 13(10): 1089-1101.
doi: 10.1016/j.jpha.2023.06.010
摘要：
Catalpol, an iridoid glucoside isolated from Rehmannia glutinosa, has gained attention due to its potential use in treating cardio-cerebrovascular diseases (CVDs). This extensive review delves into recent studies on catalpol's protective properties in relation to various CVDs, such as atherosclerosis, myocardial ischemia, infarction, cardiac hypertrophy, and heart failure. The review also explores the compound's anti-oxidant, anti-inflammatory, and anti-apoptotic characteristics, emphasizing the role of vital signaling pathways, including PGC-1α/TERT, PI3K/Akt, AMPK, Nrf2/HO-1, estrogen receptor (ER), Nox4/NF-κB, and GRP78/PERK. The article discusses emerging findings on catalpol's ability to alleviate diabetic cardiovascular complications, thrombosis, and other cardiovascular-related conditions. Although clinical studies specifically addressing catalpol's impact on CVDs are scarce, the compound's established safety and well-tolerated nature suggest that it could be a valuable treatment alternative for CVD patients. Further investigation into catalpol and related iridoid derivatives may unveil new opportunities for devising natural and efficacious CVD therapies.
Catalpol, an iridoid glucoside isolated from Rehmannia glutinosa, has gained attention due to its potential use in treating cardio-cerebrovascular diseases (CVDs). This extensive review delves into recent studies on catalpol's protective properties in relation to various CVDs, such as atherosclerosis, myocardial ischemia, infarction, cardiac hypertrophy, and heart failure. The review also explores the compound's anti-oxidant, anti-inflammatory, and anti-apoptotic characteristics, emphasizing the role of vital signaling pathways, including PGC-1α/TERT, PI3K/Akt, AMPK, Nrf2/HO-1, estrogen receptor (ER), Nox4/NF-κB, and GRP78/PERK. The article discusses emerging findings on catalpol's ability to alleviate diabetic cardiovascular complications, thrombosis, and other cardiovascular-related conditions. Although clinical studies specifically addressing catalpol's impact on CVDs are scarce, the compound's established safety and well-tolerated nature suggest that it could be a valuable treatment alternative for CVD patients. Further investigation into catalpol and related iridoid derivatives may unveil new opportunities for devising natural and efficacious CVD therapies.
2024, 14(2): 157-176.
doi: 10.1016/j.jpha.2023.09.001
摘要：
Heart failure (HF) is a highly morbid syndrome that seriously affects the physical and mental health of patients and generates an enormous socio-economic burden. In addition to cardiac myocyte oxidative stress and apoptosis, which are considered mechanisms for the development of HF, alterations in cardiac energy metabolism and pathological autophagy also contribute to cardiac abnormalities and ultimately HF. Silent information regulator 1 (Sirt1) and adenosine monophosphate-activated protein kinase (AMPK) are nicotinamide adenine dinucleotide (NAD+)-dependent deacetylases and phosphorylated kinases, respectively. They play similar roles in regulating some pathological processes of the heart through regulating targets such as peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α), protein 38 mitogen-activated protein kinase (p38 MAPK), peroxisome proliferator-activated receptors (PPARs), and mammalian target of rapamycin (mTOR). We summarized the synergistic effects of Sirt1 and AMPK in the heart, and listed the traditional Chinese medicine (TCM) that exhibit cardioprotective properties by modulating the Sirt1/AMPK pathway, to provide a basis for the development of Sirt1/AMPK activators or inhibitors for the treatment of HF and other cardiovascular diseases (CVDs).
Heart failure (HF) is a highly morbid syndrome that seriously affects the physical and mental health of patients and generates an enormous socio-economic burden. In addition to cardiac myocyte oxidative stress and apoptosis, which are considered mechanisms for the development of HF, alterations in cardiac energy metabolism and pathological autophagy also contribute to cardiac abnormalities and ultimately HF. Silent information regulator 1 (Sirt1) and adenosine monophosphate-activated protein kinase (AMPK) are nicotinamide adenine dinucleotide (NAD+)-dependent deacetylases and phosphorylated kinases, respectively. They play similar roles in regulating some pathological processes of the heart through regulating targets such as peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α), protein 38 mitogen-activated protein kinase (p38 MAPK), peroxisome proliferator-activated receptors (PPARs), and mammalian target of rapamycin (mTOR). We summarized the synergistic effects of Sirt1 and AMPK in the heart, and listed the traditional Chinese medicine (TCM) that exhibit cardioprotective properties by modulating the Sirt1/AMPK pathway, to provide a basis for the development of Sirt1/AMPK activators or inhibitors for the treatment of HF and other cardiovascular diseases (CVDs).
2024, 14(5): 100913.
doi: 10.1016/j.jpha.2023.12.003
摘要：
Obesity and related metabolic syndromes have been recognized as important disease risks, in which the role of adipokines cannot be ignored. Adiponectin (ADP) is one of the key adipokines with various beneficial effects, including improving glucose and lipid metabolism, enhancing insulin sensitivity, reducing oxidative stress and inflammation, promoting ceramides degradation, and stimulating adipose tissue vascularity. Based on those, it can serve as a positive regulator in many metabolic syndromes, such as type 2 diabetes (T2D), cardiovascular diseases, non-alcoholic fatty liver disease (NAFLD), sarcopenia, neurodegenerative diseases, and certain cancers. Therefore, a promising therapeutic approach for treating various metabolic diseases may involve elevating ADP levels or activating ADP receptors. The modulation of ADP genes, multimerization, and secretion covers the main processes of ADP generation, providing a comprehensive orientation for the development of more appropriate therapeutic strategies. In order to have a deeper understanding of ADP, this paper will provide an all-encompassing review of ADP.
Obesity and related metabolic syndromes have been recognized as important disease risks, in which the role of adipokines cannot be ignored. Adiponectin (ADP) is one of the key adipokines with various beneficial effects, including improving glucose and lipid metabolism, enhancing insulin sensitivity, reducing oxidative stress and inflammation, promoting ceramides degradation, and stimulating adipose tissue vascularity. Based on those, it can serve as a positive regulator in many metabolic syndromes, such as type 2 diabetes (T2D), cardiovascular diseases, non-alcoholic fatty liver disease (NAFLD), sarcopenia, neurodegenerative diseases, and certain cancers. Therefore, a promising therapeutic approach for treating various metabolic diseases may involve elevating ADP levels or activating ADP receptors. The modulation of ADP genes, multimerization, and secretion covers the main processes of ADP generation, providing a comprehensive orientation for the development of more appropriate therapeutic strategies. In order to have a deeper understanding of ADP, this paper will provide an all-encompassing review of ADP.
2022, 12(1): 65-76.
doi: 10.1016/j.jpha.2021.01.005
摘要：
Chronic superficial gastritis (CSG) is a common disease of the digestive system that possesses a serious pathogenesis. Jinhong tablet (JHT), a traditional Chinese medicine (TCM) prescription, exerts therapeutic effects against CSG. However, the molecular basis of its therapeutic effect has not been clarified. Herein, we employed ultra-performance liquid chromatography coupled with quadrupole time-of-flight tandem mass spectrometry (UPLC-Q/TOF-MS) based chemical profile identification to determine the chemical components in JHT. Further, we applied network pharmacology to illustrate its molecular mechanisms. A total of 96 chemical constituents were identified in JHT, 31 of which were confirmed using reference standards. Based on the bioinformatics analysis using the symptom-guided pharmacological networks of “chi,” “blood,” “pain,” and “inflammation,” and target screening through the interaction probabilities between compounds and targets, matrix metalloproteinase 2 (MMP2), dopamine d2 receptor (DRD2), and Aldo-keto reductase family 1 member B1 (AKR1B1) were identified as key targets in the therapeutic effect exhibited by JHT against CSG. Moreover, according to the inhibitory activities presented in the literature and binding mode analysis, the structural types of alkaloids, flavonoids, organic acids, including chlorogenic acid ( 10 ), caffeic acid ( 13 ), (−)-corydalmine ( 33 ), (−)-isocorypalmine ( 36 ), isochlorogenic acid C ( 38 ), isochlorogenic acid A ( 41 ), quercetin-3-O-α-l-rhamnoside ( 42 ), isochlorogenic acid B ( 47 ), quercetin ( 63 ), and kaempferol ( 70 ) tended to show remarkable activities against CSG. Owing to the above findings, we systematically identified the chemical components of JHT and revealed its molecular mechanisms based on the symptoms associated with CSG.
Chronic superficial gastritis (CSG) is a common disease of the digestive system that possesses a serious pathogenesis. Jinhong tablet (JHT), a traditional Chinese medicine (TCM) prescription, exerts therapeutic effects against CSG. However, the molecular basis of its therapeutic effect has not been clarified. Herein, we employed ultra-performance liquid chromatography coupled with quadrupole time-of-flight tandem mass spectrometry (UPLC-Q/TOF-MS) based chemical profile identification to determine the chemical components in JHT. Further, we applied network pharmacology to illustrate its molecular mechanisms. A total of 96 chemical constituents were identified in JHT, 31 of which were confirmed using reference standards. Based on the bioinformatics analysis using the symptom-guided pharmacological networks of “chi,” “blood,” “pain,” and “inflammation,” and target screening through the interaction probabilities between compounds and targets, matrix metalloproteinase 2 (MMP2), dopamine d2 receptor (DRD2), and Aldo-keto reductase family 1 member B1 (AKR1B1) were identified as key targets in the therapeutic effect exhibited by JHT against CSG. Moreover, according to the inhibitory activities presented in the literature and binding mode analysis, the structural types of alkaloids, flavonoids, organic acids, including chlorogenic acid ( 10 ), caffeic acid ( 13 ), (−)-corydalmine ( 33 ), (−)-isocorypalmine ( 36 ), isochlorogenic acid C ( 38 ), isochlorogenic acid A ( 41 ), quercetin-3-O-α-l-rhamnoside ( 42 ), isochlorogenic acid B ( 47 ), quercetin ( 63 ), and kaempferol ( 70 ) tended to show remarkable activities against CSG. Owing to the above findings, we systematically identified the chemical components of JHT and revealed its molecular mechanisms based on the symptoms associated with CSG.
2022, 12(2): 243-252.
doi: 10.1016/j.jpha.2021.04.003
摘要：
Viscum coloratum (Kom.) Nakai is a well-known medicinal hemiparasite widely distributed in Asia. The synthesis and accumulation of its metabolites are affected by both environmental factors and the host plants, while the latter of which is usually overlooked. The purpose of this study was to comprehensively evaluate the effects of host and habitat on the metabolites in V. coloratum through multiple chemical and biological approaches. The metabolite profile of V. coloratum harvested from three different host plants in two habitats were determined by multiple chemical methods including high-performance liquid chromatography-ultraviolet (HPLC-UV), gas chromatography-flame ionization detector (GC-FID) and ultra-performance liquid chromatography quadrupole time of flight mass spectrometry (UPLC-QTOF/MS). The differences in antioxidant efficacy of V. coloratum were determined based on multiple in vitro models. The multivariate statistical analysis and data fusion strategy were applied to analyze the differences in metabolite profile and antioxidant activity of V. coloratum. Results indicated that the metabolite profile obtained by various chemical approaches was simultaneously affected by host and environment factors, and the environment plays a key role. Meanwhile, three main differential metabolites between two environment groups were identified. The results of antioxidant assay indicated that the environment has greater effects on the biological activity of V. coloratum than the host. Therefore, we conclude that the integration of various chemical and biological approaches combined with multivariate statistical and data fusion analysis, which can determine the influences of host plant and habitat on the metabolites, is a powerful strategy to control the quality of semi-parasitic herbal medicine.
Viscum coloratum (Kom.) Nakai is a well-known medicinal hemiparasite widely distributed in Asia. The synthesis and accumulation of its metabolites are affected by both environmental factors and the host plants, while the latter of which is usually overlooked. The purpose of this study was to comprehensively evaluate the effects of host and habitat on the metabolites in V. coloratum through multiple chemical and biological approaches. The metabolite profile of V. coloratum harvested from three different host plants in two habitats were determined by multiple chemical methods including high-performance liquid chromatography-ultraviolet (HPLC-UV), gas chromatography-flame ionization detector (GC-FID) and ultra-performance liquid chromatography quadrupole time of flight mass spectrometry (UPLC-QTOF/MS). The differences in antioxidant efficacy of V. coloratum were determined based on multiple in vitro models. The multivariate statistical analysis and data fusion strategy were applied to analyze the differences in metabolite profile and antioxidant activity of V. coloratum. Results indicated that the metabolite profile obtained by various chemical approaches was simultaneously affected by host and environment factors, and the environment plays a key role. Meanwhile, three main differential metabolites between two environment groups were identified. The results of antioxidant assay indicated that the environment has greater effects on the biological activity of V. coloratum than the host. Therefore, we conclude that the integration of various chemical and biological approaches combined with multivariate statistical and data fusion analysis, which can determine the influences of host plant and habitat on the metabolites, is a powerful strategy to control the quality of semi-parasitic herbal medicine.
2022, 12(6): 869-878.
doi: 10.1016/j.jpha.2022.09.001
摘要：
Despite advances in immunotherapy for the treatment of cancers, not all patients can benefit from programmed cell death ligand 1 (PD-L1) immune checkpoint blockade therapy. Anti-PD-L1 therapeutic effects reportedly correlate with the PD-L1 expression level; hence, accurate detection of PD-L1 expression can guide immunotherapy to achieve better therapeutic effects. Therefore, based on the high affinity antibody Nb109, a new site-specifically radiolabeled tracer, 68Ga-NODA-cysteine, aspartic acid, and valine (CDV)-Nb109, was designed and synthesized to accurately monitor PD-L1 expression. The tracer 68Ga-NODA-CDV-Nb109 was obtained using a site-specific conjugation strategy with a radiochemical yield of about 95% and radiochemical purity of 97%. It showed high affinity for PD-L1 with a dissociation constant of 12.34 ± 1.65 nM. Both the cell uptake assay and positron emission tomography (PET) imaging revealed higher tracer uptake in PD-L1-positive A375-hPD-L1 and U87 tumor cells than in PD-L1-negative A375 tumor cells. Meanwhile, dynamic PET imaging of a NCI-H1299 xenograft indicated that doxorubicin could upregulate PD-L1 expression, allowing timely interventional immunotherapy. In conclusion, this tracer could sensitively and dynamically monitor changes in PD-L1 expression levels in different cancers and help screen patients who can benefit from anti-PD-L1 immunotherapy.
Despite advances in immunotherapy for the treatment of cancers, not all patients can benefit from programmed cell death ligand 1 (PD-L1) immune checkpoint blockade therapy. Anti-PD-L1 therapeutic effects reportedly correlate with the PD-L1 expression level; hence, accurate detection of PD-L1 expression can guide immunotherapy to achieve better therapeutic effects. Therefore, based on the high affinity antibody Nb109, a new site-specifically radiolabeled tracer, 68Ga-NODA-cysteine, aspartic acid, and valine (CDV)-Nb109, was designed and synthesized to accurately monitor PD-L1 expression. The tracer 68Ga-NODA-CDV-Nb109 was obtained using a site-specific conjugation strategy with a radiochemical yield of about 95% and radiochemical purity of 97%. It showed high affinity for PD-L1 with a dissociation constant of 12.34 ± 1.65 nM. Both the cell uptake assay and positron emission tomography (PET) imaging revealed higher tracer uptake in PD-L1-positive A375-hPD-L1 and U87 tumor cells than in PD-L1-negative A375 tumor cells. Meanwhile, dynamic PET imaging of a NCI-H1299 xenograft indicated that doxorubicin could upregulate PD-L1 expression, allowing timely interventional immunotherapy. In conclusion, this tracer could sensitively and dynamically monitor changes in PD-L1 expression levels in different cancers and help screen patients who can benefit from anti-PD-L1 immunotherapy.
2023, 13(1): 39-54.
doi: 10.1016/j.jpha.2022.11.005
摘要：
Polyphyllin I (PPI) and polyphyllin II (PII) are the main active substances in the Paris polyphylla. However, liver toxicity of these compounds has impeded their clinical application and the potential hepatotoxicity mechanisms remain to be elucidated. In this work, we found that PPI and PII exposure could induce significant hepatotoxicity in human liver cell line L-02 and zebrafish in a dose-dependent manner. The results of the proteomic analysis in L-02 cells and transcriptome in zebrafish indicated that the hepatotoxicity of PPI and PII was associated with the cholesterol biosynthetic pathway disorders, which were alleviated by the cholesterol biosynthesis inhibitor lovastatin. Additionally, 3-hydroxy-3-methy-lglutaryl CoA reductase (HMGCR) and squalene epoxidase (SQLE), the two rate-limiting enzymes in the cholesterol synthesis, selected as the potential targets, were confirmed by the molecular docking, the overexpression, and knockdown of HMGCR or SQLE with siRNA. Finally, the pull-down and surface plasmon resonance technology revealed that PPI could directly bind with SQLE but not with HMGCR. Collectively, these data demonstrated that PPI-induced hepatotoxicity resulted from the direct binding with SQLE protein and impaired the sterol-regulatory element binding protein 2/HMGCR/SQLE/lanosterol synthase pathways, thus disturbing the cholesterol biosynthesis pathway. The findings of this research can contribute to a better understanding of the key role of SQLE as a potential target in drug-induced hepatotoxicity and provide a therapeutic strategy for the prevention of drug toxic effects with similar structures in the future.
Polyphyllin I (PPI) and polyphyllin II (PII) are the main active substances in the Paris polyphylla. However, liver toxicity of these compounds has impeded their clinical application and the potential hepatotoxicity mechanisms remain to be elucidated. In this work, we found that PPI and PII exposure could induce significant hepatotoxicity in human liver cell line L-02 and zebrafish in a dose-dependent manner. The results of the proteomic analysis in L-02 cells and transcriptome in zebrafish indicated that the hepatotoxicity of PPI and PII was associated with the cholesterol biosynthetic pathway disorders, which were alleviated by the cholesterol biosynthesis inhibitor lovastatin. Additionally, 3-hydroxy-3-methy-lglutaryl CoA reductase (HMGCR) and squalene epoxidase (SQLE), the two rate-limiting enzymes in the cholesterol synthesis, selected as the potential targets, were confirmed by the molecular docking, the overexpression, and knockdown of HMGCR or SQLE with siRNA. Finally, the pull-down and surface plasmon resonance technology revealed that PPI could directly bind with SQLE but not with HMGCR. Collectively, these data demonstrated that PPI-induced hepatotoxicity resulted from the direct binding with SQLE protein and impaired the sterol-regulatory element binding protein 2/HMGCR/SQLE/lanosterol synthase pathways, thus disturbing the cholesterol biosynthesis pathway. The findings of this research can contribute to a better understanding of the key role of SQLE as a potential target in drug-induced hepatotoxicity and provide a therapeutic strategy for the prevention of drug toxic effects with similar structures in the future.
2023, 13(9): 999-1012.
doi: 10.1016/j.jpha.2023.05.005
摘要：
Heavy alcohol consumption results in alcoholic liver disease (ALD) with inadequate therapeutic options. Here, we first report the potential beneficial effects of ginsenoside Rk2 (Rk2), a rare dehydroprotopanaxadiol saponin isolated from streamed ginseng, against alcoholic liver injury in mice. Chronic-plus-single-binge ethanol feeding caused severe liver injury, as manifested by significantly elevated serum aminotransferase levels, hepatic histological changes, increased lipid accumulation, oxidative stress, and inflammation in the liver. These deleterious effects were alleviated by the treatment with Rk2 (5 and 30 mg/kg). Acting as an nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inhibitor, Rk2 ameliorates alcohol-induced liver inflammation by inhibiting NLRP3 inflammasome signaling in the liver. Meanwhile, the treatment with Rk2 alleviated the alcohol-induced intestinal barrier dysfunction via enhancing NLRP6 inflammasome in the intestine. Our findings indicate that Rk2 is a promising agent for the prevention and treatment of ALD and other NLPR3-driven diseases.
Heavy alcohol consumption results in alcoholic liver disease (ALD) with inadequate therapeutic options. Here, we first report the potential beneficial effects of ginsenoside Rk2 (Rk2), a rare dehydroprotopanaxadiol saponin isolated from streamed ginseng, against alcoholic liver injury in mice. Chronic-plus-single-binge ethanol feeding caused severe liver injury, as manifested by significantly elevated serum aminotransferase levels, hepatic histological changes, increased lipid accumulation, oxidative stress, and inflammation in the liver. These deleterious effects were alleviated by the treatment with Rk2 (5 and 30 mg/kg). Acting as an nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inhibitor, Rk2 ameliorates alcohol-induced liver inflammation by inhibiting NLRP3 inflammasome signaling in the liver. Meanwhile, the treatment with Rk2 alleviated the alcohol-induced intestinal barrier dysfunction via enhancing NLRP6 inflammasome in the intestine. Our findings indicate that Rk2 is a promising agent for the prevention and treatment of ALD and other NLPR3-driven diseases.
2023, 13(10): 1153-1167.
doi: 10.1016/j.jpha.2023.06.007
摘要：
It is necessary to explore potent therapeutic agents via regulating gut microbiota and metabolism to combat Parkinson's disease (PD). Dioscin, a bioactive steroidal saponin, shows various activities. However, its effects and mechanisms against PD are limited. In this study, dioscin dramatically alleviated neuroinflammation and oxidative stress, and restored the disorders of mice induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). 16 S rDNA sequencing assay demonstrated that dioscin reversed MPTP-induced gut dysbiosis to decrease Firmicutes-to-Bacteroidetes ratio and the abundances of Enterococcus, Streptococcus, Bacteroides and Lactobacillus genera, which further inhibited bile salt hydrolase (BSH) activity and blocked bile acid (BA) deconjugation. Fecal microbiome transplantation test showed that the anti-PD effect of dioscin was gut microbiota-dependent. In addition, non-targeted fecal metabolomics assays revealed many differential metabolites in adjusting steroid biosynthesis and primary bile acid biosynthesis. Moreover, targeted bile acid metabolomics assay indicated that dioscin increased the levels of ursodeoxycholic acid, tauroursodeoxycholic acid, taurodeoxycholic acid and β-muricholic acid in feces and serum. In addition, ursodeoxycholic acid administration markedly improved the protective effects of dioscin against PD in mice. Mechanistic test indicated that dioscin significantly up-regulated the levels of takeda G protein-coupled receptor 5 (TGR5), glucagon-like peptide-1 receptor (GLP-1R), GLP-1, superoxide dismutase (SOD), and down-regulated NADPH oxidases 2 (NOX2) and nuclear factor-kappaB (NF-κB) levels. Our data indicated that dioscin ameliorated PD phenotype by restoring gut dysbiosis and regulating bile acid-mediated oxidative stress and neuroinflammation via targeting GLP-1 signal in MPTP-induced PD mice, suggesting that the compound should be considered as a prebiotic agent to treat PD in the future.
It is necessary to explore potent therapeutic agents via regulating gut microbiota and metabolism to combat Parkinson's disease (PD). Dioscin, a bioactive steroidal saponin, shows various activities. However, its effects and mechanisms against PD are limited. In this study, dioscin dramatically alleviated neuroinflammation and oxidative stress, and restored the disorders of mice induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). 16 S rDNA sequencing assay demonstrated that dioscin reversed MPTP-induced gut dysbiosis to decrease Firmicutes-to-Bacteroidetes ratio and the abundances of Enterococcus, Streptococcus, Bacteroides and Lactobacillus genera, which further inhibited bile salt hydrolase (BSH) activity and blocked bile acid (BA) deconjugation. Fecal microbiome transplantation test showed that the anti-PD effect of dioscin was gut microbiota-dependent. In addition, non-targeted fecal metabolomics assays revealed many differential metabolites in adjusting steroid biosynthesis and primary bile acid biosynthesis. Moreover, targeted bile acid metabolomics assay indicated that dioscin increased the levels of ursodeoxycholic acid, tauroursodeoxycholic acid, taurodeoxycholic acid and β-muricholic acid in feces and serum. In addition, ursodeoxycholic acid administration markedly improved the protective effects of dioscin against PD in mice. Mechanistic test indicated that dioscin significantly up-regulated the levels of takeda G protein-coupled receptor 5 (TGR5), glucagon-like peptide-1 receptor (GLP-1R), GLP-1, superoxide dismutase (SOD), and down-regulated NADPH oxidases 2 (NOX2) and nuclear factor-kappaB (NF-κB) levels. Our data indicated that dioscin ameliorated PD phenotype by restoring gut dysbiosis and regulating bile acid-mediated oxidative stress and neuroinflammation via targeting GLP-1 signal in MPTP-induced PD mice, suggesting that the compound should be considered as a prebiotic agent to treat PD in the future.
2023, 13(11): 1252-1268.
doi: 10.1016/j.jpha.2023.08.020
摘要：
Waterborne viruses that can be harmful to human health pose significant challenges globally, affecting health care systems and the economy. Identifying these waterborne pathogens is essential for preventing diseases and protecting public health. However, handling complex samples such as human and wastewater can be challenging due to their dynamic and complex composition and the ultralow concentration of target analytes. This review presents a comprehensive overview of the latest breakthroughs in waterborne virus biosensors. It begins by highlighting several promising strategies that enhance the sensing performance of optical and electrochemical biosensors in human samples. These strategies include optimizing bioreceptor selection, transduction elements, signal amplification, and integrated sensing systems. Furthermore, the insights gained from biosensing waterborne viruses in human samples are applied to improve biosensing in wastewater, with a particular focus on sampling and sample pretreatment due to the dispersion characteristics of waterborne viruses in wastewater. This review suggests that implementing a comprehensive system that integrates the entire waterborne virus detection process with high-accuracy analysis could enhance virus monitoring. These findings provide valuable insights for improving the effectiveness of waterborne virus detection, which could have significant implications for public health and environmental management.
Waterborne viruses that can be harmful to human health pose significant challenges globally, affecting health care systems and the economy. Identifying these waterborne pathogens is essential for preventing diseases and protecting public health. However, handling complex samples such as human and wastewater can be challenging due to their dynamic and complex composition and the ultralow concentration of target analytes. This review presents a comprehensive overview of the latest breakthroughs in waterborne virus biosensors. It begins by highlighting several promising strategies that enhance the sensing performance of optical and electrochemical biosensors in human samples. These strategies include optimizing bioreceptor selection, transduction elements, signal amplification, and integrated sensing systems. Furthermore, the insights gained from biosensing waterborne viruses in human samples are applied to improve biosensing in wastewater, with a particular focus on sampling and sample pretreatment due to the dispersion characteristics of waterborne viruses in wastewater. This review suggests that implementing a comprehensive system that integrates the entire waterborne virus detection process with high-accuracy analysis could enhance virus monitoring. These findings provide valuable insights for improving the effectiveness of waterborne virus detection, which could have significant implications for public health and environmental management.
2023, 13(12): 1496-1509.
doi: 10.1016/j.jpha.2023.08.011
摘要：
Diabetic cardiomyopathy (DCM) is a metabolic disease and a leading cause of heart failure among people with diabetes. Mass spectrometry imaging (MSI) is a versatile technique capable of combining the molecular specificity of mass spectrometry (MS) with the spatial information of imaging. In this study, we used MSI to visualize metabolites in the rat heart with high spatial resolution and sensitivity. We optimized the air flow-assisted desorption electrospray ionization (AFADESI)-MSI platform to detect a wide range of metabolites, and then used matrix-assisted laser desorption ionization (MALDI)-MSI for increasing metabolic coverage and improving localization resolution. AFADESI-MSI detected 214 and 149 metabolites in positive and negative analyses of rat heart sections, respectively, while MALDI-MSI detected 61 metabolites in negative analysis. Our study revealed the heterogenous metabolic profile of the heart in a DCM model, with over 105 region-specific changes in the levels of a wide range of metabolite classes, including carbohydrates, amino acids, nucleotides, and their derivatives, fatty acids, glycerol phospholipids, carnitines, and metal ions. The repeated oral administration of ferulic acid during 20 weeks significantly improved most of the metabolic disorders in the DCM model. Our findings provide novel insights into the molecular mechanisms underlying DCM and the potential of ferulic acid as a therapeutic agent for treating this condition.
Diabetic cardiomyopathy (DCM) is a metabolic disease and a leading cause of heart failure among people with diabetes. Mass spectrometry imaging (MSI) is a versatile technique capable of combining the molecular specificity of mass spectrometry (MS) with the spatial information of imaging. In this study, we used MSI to visualize metabolites in the rat heart with high spatial resolution and sensitivity. We optimized the air flow-assisted desorption electrospray ionization (AFADESI)-MSI platform to detect a wide range of metabolites, and then used matrix-assisted laser desorption ionization (MALDI)-MSI for increasing metabolic coverage and improving localization resolution. AFADESI-MSI detected 214 and 149 metabolites in positive and negative analyses of rat heart sections, respectively, while MALDI-MSI detected 61 metabolites in negative analysis. Our study revealed the heterogenous metabolic profile of the heart in a DCM model, with over 105 region-specific changes in the levels of a wide range of metabolite classes, including carbohydrates, amino acids, nucleotides, and their derivatives, fatty acids, glycerol phospholipids, carnitines, and metal ions. The repeated oral administration of ferulic acid during 20 weeks significantly improved most of the metabolic disorders in the DCM model. Our findings provide novel insights into the molecular mechanisms underlying DCM and the potential of ferulic acid as a therapeutic agent for treating this condition.
2024, 14(4): 100899.
doi: 10.1016/j.jpha.2023.11.006
摘要：
Tyrosine kinase inhibitors (TKIs) have emerged as the first-line small molecule drugs in many cancer therapies, exerting their effects by impeding aberrant cell growth and proliferation through the modulation of tyrosine kinase-mediated signaling pathways. However, there exists a substantial inter-individual variability in the concentrations of certain TKIs and their metabolites, which may render patients with compromised immune function susceptible to diverse infections despite receiving theoretically efficacious anticancer treatments, alongside other potential side effects or adverse reactions. Therefore, an urgent need exists for an up-to-date review concerning the biological matrices relevant to bioanalysis and the sampling methods, clinical pharmacokinetics, and therapeutic drug monitoring of different TKIs. This paper provides a comprehensive overview of the advancements in pretreatment methods, such as protein precipitation (PPT), liquid-liquid extraction (LLE), solid-phase extraction (SPE), micro-SPE (μ-SPE), magnetic SPE (MSPE), and vortex-assisted dispersive SPE (VA-DSPE) achieved since 2017. It also highlights the latest analysis techniques such as newly developed high performance liquid chromatography (HPLC) and high-resolution mass spectrometry (HRMS) methods, capillary electrophoresis (CE), gas chromatography (GC), supercritical fluid chromatography (SFC) procedures, surface plasmon resonance (SPR) assays as well as novel nanoprobes-based biosensing techniques. In addition, a comparison is made between the advantages and disadvantages of different approaches while presenting critical challenges and prospects in pharmacokinetic studies and therapeutic drug monitoring.
Tyrosine kinase inhibitors (TKIs) have emerged as the first-line small molecule drugs in many cancer therapies, exerting their effects by impeding aberrant cell growth and proliferation through the modulation of tyrosine kinase-mediated signaling pathways. However, there exists a substantial inter-individual variability in the concentrations of certain TKIs and their metabolites, which may render patients with compromised immune function susceptible to diverse infections despite receiving theoretically efficacious anticancer treatments, alongside other potential side effects or adverse reactions. Therefore, an urgent need exists for an up-to-date review concerning the biological matrices relevant to bioanalysis and the sampling methods, clinical pharmacokinetics, and therapeutic drug monitoring of different TKIs. This paper provides a comprehensive overview of the advancements in pretreatment methods, such as protein precipitation (PPT), liquid-liquid extraction (LLE), solid-phase extraction (SPE), micro-SPE (μ-SPE), magnetic SPE (MSPE), and vortex-assisted dispersive SPE (VA-DSPE) achieved since 2017. It also highlights the latest analysis techniques such as newly developed high performance liquid chromatography (HPLC) and high-resolution mass spectrometry (HRMS) methods, capillary electrophoresis (CE), gas chromatography (GC), supercritical fluid chromatography (SFC) procedures, surface plasmon resonance (SPR) assays as well as novel nanoprobes-based biosensing techniques. In addition, a comparison is made between the advantages and disadvantages of different approaches while presenting critical challenges and prospects in pharmacokinetic studies and therapeutic drug monitoring.
2022, 12(3): 424-435.
doi: 10.1016/j.jpha.2021.09.010
摘要：
One of the challenges in developing three-dimensional printed medicines is related to their stability due to the manufacturing conditions involving high temperatures. This work proposed a new protocol for preformulation studies simulating thermal processing and aging of the printed medicines, tested regarding their morphology and thermal, crystallographic, and spectroscopic profiles. Generally, despite the strong drug-polymer interactions observed, the chemical stability of the model drugs was preserved under such conditions. In fact, in the metoprolol and Soluplus® composition, the drug's solubilization in the polymer produced a delay in the drug decomposition, suggesting a protective effect of the matrix. Paracetamol and polyvinyl alcohol mixture, in turn, showed unmistakable signs of thermal instability and chemical decomposition, in addition to physical changes. In the presented context, establishing protocols that simulate processing and storage conditions may be decisive for obtaining stable pharmaceutical dosage forms using three-dimensional printing technology.
One of the challenges in developing three-dimensional printed medicines is related to their stability due to the manufacturing conditions involving high temperatures. This work proposed a new protocol for preformulation studies simulating thermal processing and aging of the printed medicines, tested regarding their morphology and thermal, crystallographic, and spectroscopic profiles. Generally, despite the strong drug-polymer interactions observed, the chemical stability of the model drugs was preserved under such conditions. In fact, in the metoprolol and Soluplus® composition, the drug's solubilization in the polymer produced a delay in the drug decomposition, suggesting a protective effect of the matrix. Paracetamol and polyvinyl alcohol mixture, in turn, showed unmistakable signs of thermal instability and chemical decomposition, in addition to physical changes. In the presented context, establishing protocols that simulate processing and storage conditions may be decisive for obtaining stable pharmaceutical dosage forms using three-dimensional printing technology.
2022, 12(4): 617-626.
doi: 10.1016/j.jpha.2022.01.002
摘要：
An innovative sandwich-structural Fe-based metal-organic framework magnetic material (Fe3O4@SW-MIL-101-NH2) was fabricated using a facile solvothermal method. The characteristic properties of the material were investigated by field emission scanning electron microscopy, transmission electron microscopy (TEM), energy-dispersive X-ray spectroscopy, Fourier transform infrared spectroscopy, X-ray powder diffraction, vibrating sample magnetometry, and Brunauer-Emmett-Teller measurements. Fe3O4@SW-MIL-101-NH2 is associated with advantages, such as robust magnetic properties, high specific surface area, and satisfactory storage stability, as well as good selective recognition ability for chlorogenic acid (CA) and its metabolites via chelation, hydrogen bonding, and π-interaction. The results of the static adsorption experiment indicated that Fe3O4@SW-MIL-101-NH2 possessed a high adsorption capacity toward CA and its isomers, cryptochlorogenic acid (CCA) and neochlorogenic acid (NCA), and the adsorption behaviors were fitted using the Langmuir adsorption isotherm model. Then, a strategy using magnetic solid-phase extraction (MSPE) and ultra-performance liquid chromatography coupled with quadrupole time-of-flight tandem mass spectrometry (UPLC-Q-TOF MS/MS) was developed and successfully employed for the selective pre-concentration and rapid identification of CA metabolites in rat plasma, urine, and feces samples. This work presents a prospective strategy for the synthesis of magnetic adsorbents and the high-efficiency pretreatment of CA metabolites.
An innovative sandwich-structural Fe-based metal-organic framework magnetic material (Fe3O4@SW-MIL-101-NH2) was fabricated using a facile solvothermal method. The characteristic properties of the material were investigated by field emission scanning electron microscopy, transmission electron microscopy (TEM), energy-dispersive X-ray spectroscopy, Fourier transform infrared spectroscopy, X-ray powder diffraction, vibrating sample magnetometry, and Brunauer-Emmett-Teller measurements. Fe3O4@SW-MIL-101-NH2 is associated with advantages, such as robust magnetic properties, high specific surface area, and satisfactory storage stability, as well as good selective recognition ability for chlorogenic acid (CA) and its metabolites via chelation, hydrogen bonding, and π-interaction. The results of the static adsorption experiment indicated that Fe3O4@SW-MIL-101-NH2 possessed a high adsorption capacity toward CA and its isomers, cryptochlorogenic acid (CCA) and neochlorogenic acid (NCA), and the adsorption behaviors were fitted using the Langmuir adsorption isotherm model. Then, a strategy using magnetic solid-phase extraction (MSPE) and ultra-performance liquid chromatography coupled with quadrupole time-of-flight tandem mass spectrometry (UPLC-Q-TOF MS/MS) was developed and successfully employed for the selective pre-concentration and rapid identification of CA metabolites in rat plasma, urine, and feces samples. This work presents a prospective strategy for the synthesis of magnetic adsorbents and the high-efficiency pretreatment of CA metabolites.
2022, 12(6): 879-888.
doi: 10.1016/j.jpha.2022.07.002
摘要：
The composition of serum is extremely complex, which complicates the discovery of new pharmacodynamic biomarkers via serum proteome for disease prediction and diagnosis. Recently, nanoparticles have been reported to efficiently reduce the proportion of high-abundance proteins and enrich low-abundance proteins in serum. Here, we synthesized a silica-coated iron oxide nanoparticle and developed a highly efficient and reproducible protein corona (PC)-based proteomic analysis strategy to improve the range of serum proteomic analysis. We identified 1,070 proteins with a median coefficient of variation of 12.56% using PC-based proteomic analysis, which was twice the number of proteins identified by direct digestion. There were also more biological processes enriched with these proteins. We applied this strategy to identify more pharmacodynamic biomarkers on collagen-induced arthritis (CIA) rat model treated with methotrexate (MTX). The bioinformatic results indicated that 485 differentially expressed proteins (DEPs) were found in CIA rats, of which 323 DEPs recovered to near normal levels after treatment with MTX. This strategy can not only help enhance our understanding of the mechanisms of disease and drug action through serum proteomics studies, but also provide more pharmacodynamic biomarkers for disease prediction, diagnosis, and treatment.
The composition of serum is extremely complex, which complicates the discovery of new pharmacodynamic biomarkers via serum proteome for disease prediction and diagnosis. Recently, nanoparticles have been reported to efficiently reduce the proportion of high-abundance proteins and enrich low-abundance proteins in serum. Here, we synthesized a silica-coated iron oxide nanoparticle and developed a highly efficient and reproducible protein corona (PC)-based proteomic analysis strategy to improve the range of serum proteomic analysis. We identified 1,070 proteins with a median coefficient of variation of 12.56% using PC-based proteomic analysis, which was twice the number of proteins identified by direct digestion. There were also more biological processes enriched with these proteins. We applied this strategy to identify more pharmacodynamic biomarkers on collagen-induced arthritis (CIA) rat model treated with methotrexate (MTX). The bioinformatic results indicated that 485 differentially expressed proteins (DEPs) were found in CIA rats, of which 323 DEPs recovered to near normal levels after treatment with MTX. This strategy can not only help enhance our understanding of the mechanisms of disease and drug action through serum proteomics studies, but also provide more pharmacodynamic biomarkers for disease prediction, diagnosis, and treatment.
2023, 13(1): 88-98.
doi: 10.1016/j.jpha.2022.11.007
摘要：
Aconitine, a common and main toxic component of Aconitum, is toxic to the central nervous system. However, the mechanism of aconitine neurotoxicity is not yet clear. In this work, we had the hypothesis that excitatory amino acids can trigger excitotoxicity as a pointcut to explore the mechanism of neurotoxicity induced by aconitine. HT22 cells were simulated by aconitine and the changes of target cell metabolites were real-time online investigated based on a microfluidic chip-mass spectrometry system. Meanwhile, to confirm the metabolic mechanism of aconitine toxicity on HT22 cells, the levels of lactate dehydrogenase, intracellular Ca2+, reactive oxygen species, glutathione and superoxide dismutase, and ratio of Bax/Bcl-2 protein were detected by molecular biotechnology. Integration of the detected results revealed that neurotoxicity induced by aconitine was associated with the process of excitotoxicity caused by glutamic acid and aspartic acid, which was followed by the accumulation of lactic acid and reduction of glucose. The surge of extracellular glutamic acid could further lead to a series of cascade reactions including intracellular Ca2+ overload and oxidative stress, and eventually result in cell apoptosis. In general, we illustrated a new mechanism of aconitine neurotoxicity and presented a novel analysis strategy that real-time online monitoring of cell metabolites can provide a new approach to mechanism analysis.
Aconitine, a common and main toxic component of Aconitum, is toxic to the central nervous system. However, the mechanism of aconitine neurotoxicity is not yet clear. In this work, we had the hypothesis that excitatory amino acids can trigger excitotoxicity as a pointcut to explore the mechanism of neurotoxicity induced by aconitine. HT22 cells were simulated by aconitine and the changes of target cell metabolites were real-time online investigated based on a microfluidic chip-mass spectrometry system. Meanwhile, to confirm the metabolic mechanism of aconitine toxicity on HT22 cells, the levels of lactate dehydrogenase, intracellular Ca2+, reactive oxygen species, glutathione and superoxide dismutase, and ratio of Bax/Bcl-2 protein were detected by molecular biotechnology. Integration of the detected results revealed that neurotoxicity induced by aconitine was associated with the process of excitotoxicity caused by glutamic acid and aspartic acid, which was followed by the accumulation of lactic acid and reduction of glucose. The surge of extracellular glutamic acid could further lead to a series of cascade reactions including intracellular Ca2+ overload and oxidative stress, and eventually result in cell apoptosis. In general, we illustrated a new mechanism of aconitine neurotoxicity and presented a novel analysis strategy that real-time online monitoring of cell metabolites can provide a new approach to mechanism analysis.
2024, 14(2): 276-283.
doi: 10.1016/j.jpha.2023.09.011
摘要：
The application of pesticides (mostly insecticides and fungicides) during the tea-planting process will undoubtedly increase the dietary risk associated with drinking tea. Thus, it is necessary to ascertain whether pesticide residues in tea products exceed the maximum residue limits. However, the complex matrices present in tea samples comprise a major challenge in the analytical detection of pesticide residues. In this study, nine types of lateral flow immunochromatographic strips (LFICSs) were developed to detect the pesticides of interest (fenpropathrin, chlorpyrifos, imidacloprid, thiamethoxam, acetamiprid, carbendazim, chlorothalonil, pyraclostrobin, and iprodione). To reduce the interference of tea substrates on the assay sensitivity, the pretreatment conditions for tea samples, including the extraction solvent, extraction time, and purification agent, were optimized for the simultaneous detection of these pesticides. The entire testing procedure (including pretreatment and detection) could be completed within 30 min. The detected results of authentic tea samples were confirmed by ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS), which suggest that the LFICS coupled with sample rapid pretreatment can be used for on-site rapid screening of the target pesticide in tea products prior to their market release.
The application of pesticides (mostly insecticides and fungicides) during the tea-planting process will undoubtedly increase the dietary risk associated with drinking tea. Thus, it is necessary to ascertain whether pesticide residues in tea products exceed the maximum residue limits. However, the complex matrices present in tea samples comprise a major challenge in the analytical detection of pesticide residues. In this study, nine types of lateral flow immunochromatographic strips (LFICSs) were developed to detect the pesticides of interest (fenpropathrin, chlorpyrifos, imidacloprid, thiamethoxam, acetamiprid, carbendazim, chlorothalonil, pyraclostrobin, and iprodione). To reduce the interference of tea substrates on the assay sensitivity, the pretreatment conditions for tea samples, including the extraction solvent, extraction time, and purification agent, were optimized for the simultaneous detection of these pesticides. The entire testing procedure (including pretreatment and detection) could be completed within 30 min. The detected results of authentic tea samples were confirmed by ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS), which suggest that the LFICS coupled with sample rapid pretreatment can be used for on-site rapid screening of the target pesticide in tea products prior to their market release.
2024, 14(5): 100919.
doi: 10.1016/j.jpha.2023.12.009
摘要：
The presence of N-nitroso compounds, particularly N-nitrosamines, in pharmaceutical products has raised global safety concerns due to their significant genotoxic and mutagenic effects. This systematic review investigates their toxicity in active pharmaceutical ingredients (APIs), drug products, and pharmaceutical excipients, along with novel analytical strategies for detection, root cause analysis, reformulation strategies, and regulatory guidelines for nitrosamines. This review emphasizes the molecular toxicity of N-nitroso compounds, focusing on genotoxic, mutagenic, carcinogenic, and other physiological effects. Additionally, it addresses the ongoing nitrosamine crisis, the development of nitrosamine-free products, and the importance of sensitive detection methods and precise risk evaluation. This comprehensive overview will aid molecular biologists, analytical scientists, formulation scientists in research and development sector, and researchers involved in management of nitrosamine-induced toxicity and promoting safer pharmaceutical products.
The presence of N-nitroso compounds, particularly N-nitrosamines, in pharmaceutical products has raised global safety concerns due to their significant genotoxic and mutagenic effects. This systematic review investigates their toxicity in active pharmaceutical ingredients (APIs), drug products, and pharmaceutical excipients, along with novel analytical strategies for detection, root cause analysis, reformulation strategies, and regulatory guidelines for nitrosamines. This review emphasizes the molecular toxicity of N-nitroso compounds, focusing on genotoxic, mutagenic, carcinogenic, and other physiological effects. Additionally, it addresses the ongoing nitrosamine crisis, the development of nitrosamine-free products, and the importance of sensitive detection methods and precise risk evaluation. This comprehensive overview will aid molecular biologists, analytical scientists, formulation scientists in research and development sector, and researchers involved in management of nitrosamine-induced toxicity and promoting safer pharmaceutical products.
2022, 12(1): 145-155.
doi: 10.1016/j.jpha.2021.06.001
摘要：
The National Medical Products Administration has authorized sodium oligomannate for treating mild-to-moderate Alzheimer's disease. In this study, an LC-MS/MS method was developed and validated to quantitate sodium oligomannate in different biomatrices. The plasma pharmacokinetics, tissue distribution, and excretion of sodium oligomannate in Sprague-Dawley rats and beagle dogs were systematically investigated. Despite its complicated structural composition, the absorption, distribution, metabolism, and excretion profiles of the oligosaccharides in sodium oligomannate of different sizes and terminal derivatives were indiscriminate. Sodium oligomannate mainly crossed the gastrointestinal epithelium through paracellular transport following oral administration, with very low oral bioavailability in rats (0.6%–1.6%) and dogs (4.5%–9.3%). Absorbed sodium oligomannate mainly resided in circulating body fluids in free form with minimal distribution into erythrocytes and major tissues. Sodium oligomannate could penetrate the blood-cerebrospinal fluid (CSF) barrier of rats, showing a constant area under the concentration-time curve ratio (CSF/plasma) of approximately 5%. The cumulative urinary excretion of sodium oligomannate was commensurate with its oral bioavailability, supporting that excretion was predominantly renal, whereas no obvious biliary secretion was observed following a single oral dose to bile duct-cannulated rats. Moreover, only 33.7% (male) and 26.3% (female) of the oral dose were recovered in the rat excreta within 96 h following a single oral administration, suggesting that the intestinal flora may have ingested a portion of unabsorbed sodium oligomannate as a nutrient.
The National Medical Products Administration has authorized sodium oligomannate for treating mild-to-moderate Alzheimer's disease. In this study, an LC-MS/MS method was developed and validated to quantitate sodium oligomannate in different biomatrices. The plasma pharmacokinetics, tissue distribution, and excretion of sodium oligomannate in Sprague-Dawley rats and beagle dogs were systematically investigated. Despite its complicated structural composition, the absorption, distribution, metabolism, and excretion profiles of the oligosaccharides in sodium oligomannate of different sizes and terminal derivatives were indiscriminate. Sodium oligomannate mainly crossed the gastrointestinal epithelium through paracellular transport following oral administration, with very low oral bioavailability in rats (0.6%–1.6%) and dogs (4.5%–9.3%). Absorbed sodium oligomannate mainly resided in circulating body fluids in free form with minimal distribution into erythrocytes and major tissues. Sodium oligomannate could penetrate the blood-cerebrospinal fluid (CSF) barrier of rats, showing a constant area under the concentration-time curve ratio (CSF/plasma) of approximately 5%. The cumulative urinary excretion of sodium oligomannate was commensurate with its oral bioavailability, supporting that excretion was predominantly renal, whereas no obvious biliary secretion was observed following a single oral dose to bile duct-cannulated rats. Moreover, only 33.7% (male) and 26.3% (female) of the oral dose were recovered in the rat excreta within 96 h following a single oral administration, suggesting that the intestinal flora may have ingested a portion of unabsorbed sodium oligomannate as a nutrient.
2022, 12(6): 815-823.
doi: 10.1016/j.jpha.2021.11.001
摘要：
In recent years, scientific researchers have increasingly become interested in noninvasive sampling methods for therapeutic drug monitoring and disease diagnosis. As a result, dried saliva spot (DSS), which is a sampling technique for collecting dried saliva samples, has been widely used as an alternative matrix to serum for the detection of target molecules. Coupling the DSS method with a highly sensitive detection instrument improves the efficiency of the preparation and analysis of biological samples. Furthermore, dried blood spots, dried plasma spots, and dried matrix spots, which are similar to those of the DSS method, are discussed. Compared with alternative biological fluids used in dried spot methods, including serum, tears, urine, and plasma, saliva has the advantage of convenience in terms of sample collection from children or persons with disabilities. This review aims to provide integral strategies and guidelines for dried spot methods to analyze biological samples by illustrating several dried spot methods. Herein, we summarize recent advancements in DSS methods from June 2014 to March 2021 and discuss the advantages and disadvantages of the key aspects of this method, including sample preparation and method validation. Finally, we outline the challenges and prospects of such methods in practical applications.
In recent years, scientific researchers have increasingly become interested in noninvasive sampling methods for therapeutic drug monitoring and disease diagnosis. As a result, dried saliva spot (DSS), which is a sampling technique for collecting dried saliva samples, has been widely used as an alternative matrix to serum for the detection of target molecules. Coupling the DSS method with a highly sensitive detection instrument improves the efficiency of the preparation and analysis of biological samples. Furthermore, dried blood spots, dried plasma spots, and dried matrix spots, which are similar to those of the DSS method, are discussed. Compared with alternative biological fluids used in dried spot methods, including serum, tears, urine, and plasma, saliva has the advantage of convenience in terms of sample collection from children or persons with disabilities. This review aims to provide integral strategies and guidelines for dried spot methods to analyze biological samples by illustrating several dried spot methods. Herein, we summarize recent advancements in DSS methods from June 2014 to March 2021 and discuss the advantages and disadvantages of the key aspects of this method, including sample preparation and method validation. Finally, we outline the challenges and prospects of such methods in practical applications.
2023, 13(2): 127-141.
doi: 10.1016/j.jpha.2022.11.009
摘要：
The reversible and precise temporal and spatial regulation of histone lysine methyltransferases (KMTs) is essential for epigenome homeostasis. The dysregulation of KMTs is associated with tumor initiation, metastasis, chemoresistance, invasiveness, and the immune microenvironment. Therapeutically, their promising effects are being evaluated in diversified preclinical and clinical trials, demonstrating encouraging outcomes in multiple malignancies. In this review, we have updated recent understandings of KMTs' functions and the development of their targeted inhibitors. First, we provide an updated overview of the regulatory roles of several KMT activities in oncogenesis, tumor suppression, and immune regulation. In addition, we summarize the current targeting strategies in different cancer types and multiple ongoing clinical trials of combination therapies with KMT inhibitors. In summary, we endeavor to depict the regulation of KMT-mediated epigenetic landscape and provide potential epigenetic targets in the treatment of cancers.
The reversible and precise temporal and spatial regulation of histone lysine methyltransferases (KMTs) is essential for epigenome homeostasis. The dysregulation of KMTs is associated with tumor initiation, metastasis, chemoresistance, invasiveness, and the immune microenvironment. Therapeutically, their promising effects are being evaluated in diversified preclinical and clinical trials, demonstrating encouraging outcomes in multiple malignancies. In this review, we have updated recent understandings of KMTs' functions and the development of their targeted inhibitors. First, we provide an updated overview of the regulatory roles of several KMT activities in oncogenesis, tumor suppression, and immune regulation. In addition, we summarize the current targeting strategies in different cancer types and multiple ongoing clinical trials of combination therapies with KMT inhibitors. In summary, we endeavor to depict the regulation of KMT-mediated epigenetic landscape and provide potential epigenetic targets in the treatment of cancers.
2023, 13(2): 142-155.
doi: 10.1016/j.jpha.2022.11.011
摘要：
Complex systems exist widely, including medicines from natural products, functional foods, and biological samples. The biological activity of complex systems is often the result of the synergistic effect of multiple components. In the quality evaluation of complex samples, multicomponent quantitative analysis (MCQA) is usually needed. To overcome the difficulty in obtaining standard products, scholars have proposed achieving MCQA through the “single standard to determine multiple components (SSDMC)” approach. This method has been used in the determination of multicomponent content in natural source drugs and the analysis of impurities in chemical drugs and has been included in the Chinese Pharmacopoeia. Depending on a convenient (ultra) high-performance liquid chromatography method, how can the repeatability and robustness of the MCQA method be improved? How can the chromatography conditions be optimized to improve the number of quantitative components? How can computer software technology be introduced to improve the efficiency of multicomponent analysis (MCA)? These are the key problems that remain to be solved in practical MCQA. First, this review article summarizes the calculation methods of relative correction factors in the SSDMC approach in the past five years, as well as the method robustness and accuracy evaluation. Second, it also summarizes methods to improve peak capacity and quantitative accuracy in MCA, including column selection and two-dimensional chromatographic analysis technology. Finally, computer software technologies for predicting chromatographic conditions and analytical parameters are introduced, which provides an idea for intelligent method development in MCA. This paper aims to provide methodological ideas for the improvement of complex system analysis, especially MCQA.
Complex systems exist widely, including medicines from natural products, functional foods, and biological samples. The biological activity of complex systems is often the result of the synergistic effect of multiple components. In the quality evaluation of complex samples, multicomponent quantitative analysis (MCQA) is usually needed. To overcome the difficulty in obtaining standard products, scholars have proposed achieving MCQA through the “single standard to determine multiple components (SSDMC)” approach. This method has been used in the determination of multicomponent content in natural source drugs and the analysis of impurities in chemical drugs and has been included in the Chinese Pharmacopoeia. Depending on a convenient (ultra) high-performance liquid chromatography method, how can the repeatability and robustness of the MCQA method be improved? How can the chromatography conditions be optimized to improve the number of quantitative components? How can computer software technology be introduced to improve the efficiency of multicomponent analysis (MCA)? These are the key problems that remain to be solved in practical MCQA. First, this review article summarizes the calculation methods of relative correction factors in the SSDMC approach in the past five years, as well as the method robustness and accuracy evaluation. Second, it also summarizes methods to improve peak capacity and quantitative accuracy in MCA, including column selection and two-dimensional chromatographic analysis technology. Finally, computer software technologies for predicting chromatographic conditions and analytical parameters are introduced, which provides an idea for intelligent method development in MCA. This paper aims to provide methodological ideas for the improvement of complex system analysis, especially MCQA.
2023, 13(6): 640-659.
doi: 10.1016/j.jpha.2023.04.016
摘要：
Radix Bupleuri (RB) is commonly used to treat depression, but it can also lead to hepatotoxicity after long-term use. In many anti-depression prescriptions, RB is often used in combination with Radix Paeoniae Alba (RPA) as an herb pair. However, whether RPA can alleviate RB-induced hepatotoxicity remain unclear. In this work, the results confirmed that RB had a dose-dependent antidepressant effect, but the optimal antidepressant dose caused hepatotoxicity. Notably, RPA effectively reversed RB-induced hepatotoxicity. Afterward, the mechanism of RB-induced hepatotoxicity was confirmed. The results showed that saikosaponin A and saikosaponin D could inhibit GSH synthase (GSS) activity in the liver, and further cause liver injury through oxidative stress and nuclear factor kappa B (NF-κB)/NOD-like receptor thermal protein domain associated protein 3 (NLRP3) pathway. Furthermore, the mechanisms by which RPA attenuates RB-induced hepatotoxicity were investigated. The results demonstrated that RPA increased the abundance of intestinal bacteria with glycosidase activity, thereby promoting the conversion of saikosaponins to saikogenins in vivo. Different from saikosaponin A and saikosaponin D, which are directly combined with GSS as an inhibitor, their deglycosylation conversion products saikogenin F and saikogenin G exhibited no GSS binding activity. Based on this, RPA can alleviate the inhibitory effect of saikosaponins on GSS activity to reshape the liver redox balance and further reverse the RB-induced liver inflammatory response by the NF-κB/NLRP3 pathway. In conclusion, the present study suggests that promoting the conversion of saikosaponins by modulating gut microbiota to attenuate the inhibition of GSS is the potential mechanism by which RPA prevents RB-induced hepatotoxicity.
Radix Bupleuri (RB) is commonly used to treat depression, but it can also lead to hepatotoxicity after long-term use. In many anti-depression prescriptions, RB is often used in combination with Radix Paeoniae Alba (RPA) as an herb pair. However, whether RPA can alleviate RB-induced hepatotoxicity remain unclear. In this work, the results confirmed that RB had a dose-dependent antidepressant effect, but the optimal antidepressant dose caused hepatotoxicity. Notably, RPA effectively reversed RB-induced hepatotoxicity. Afterward, the mechanism of RB-induced hepatotoxicity was confirmed. The results showed that saikosaponin A and saikosaponin D could inhibit GSH synthase (GSS) activity in the liver, and further cause liver injury through oxidative stress and nuclear factor kappa B (NF-κB)/NOD-like receptor thermal protein domain associated protein 3 (NLRP3) pathway. Furthermore, the mechanisms by which RPA attenuates RB-induced hepatotoxicity were investigated. The results demonstrated that RPA increased the abundance of intestinal bacteria with glycosidase activity, thereby promoting the conversion of saikosaponins to saikogenins in vivo. Different from saikosaponin A and saikosaponin D, which are directly combined with GSS as an inhibitor, their deglycosylation conversion products saikogenin F and saikogenin G exhibited no GSS binding activity. Based on this, RPA can alleviate the inhibitory effect of saikosaponins on GSS activity to reshape the liver redox balance and further reverse the RB-induced liver inflammatory response by the NF-κB/NLRP3 pathway. In conclusion, the present study suggests that promoting the conversion of saikosaponins by modulating gut microbiota to attenuate the inhibition of GSS is the potential mechanism by which RPA prevents RB-induced hepatotoxicity.
2023, 13(7): 694-710.
doi: 10.1016/j.jpha.2023.04.003
摘要：
Recent studies have highlighted spatially resolved multi-omics technologies, including spatial genomics, transcriptomics, proteomics, and metabolomics, as powerful tools to decipher the spatial heterogeneity of the brain. Here, we focus on two major approaches in spatial transcriptomics (next-generation sequencing-based technologies and image-based technologies), and mass spectrometry imaging technologies used in spatial proteomics and spatial metabolomics. Furthermore, we discuss their applications in neuroscience, including building the brain atlas, uncovering gene expression patterns of neurons for special behaviors, deciphering the molecular basis of neuronal communication, and providing a more comprehensive explanation of the molecular mechanisms underlying central nervous system disorders. However, further efforts are still needed toward the integrative application of multi-omics technologies, including the real-time spatial multi-omics analysis in living cells, the detailed gene profile in a whole-brain view, and the combination of functional verification.
Recent studies have highlighted spatially resolved multi-omics technologies, including spatial genomics, transcriptomics, proteomics, and metabolomics, as powerful tools to decipher the spatial heterogeneity of the brain. Here, we focus on two major approaches in spatial transcriptomics (next-generation sequencing-based technologies and image-based technologies), and mass spectrometry imaging technologies used in spatial proteomics and spatial metabolomics. Furthermore, we discuss their applications in neuroscience, including building the brain atlas, uncovering gene expression patterns of neurons for special behaviors, deciphering the molecular basis of neuronal communication, and providing a more comprehensive explanation of the molecular mechanisms underlying central nervous system disorders. However, further efforts are still needed toward the integrative application of multi-omics technologies, including the real-time spatial multi-omics analysis in living cells, the detailed gene profile in a whole-brain view, and the combination of functional verification.
2023, 13(12): 1452-1470.
doi: 10.1016/j.jpha.2023.09.014
摘要：
Antibiotics are among the most often used medications in human healthcare and agriculture. Overusing these substances can lead to complications such as increasing antibiotic resistance in bacteria or a toxic effect when administering large amounts. To solve these problems, new solutions in antibacterial therapy are needed. The use of natural products in medicine has been known for centuries. Some of them have antibacterial activity, hence the idea to combine their activity with commercial antibiotics to reduce the latter's use. This review presents collected information on natural compounds (terpenes, alkaloids, flavonoids, tannins, sulfoxides, and mycotoxins), of which various drug interactions have been observed. Many of the indicated compounds show synergistic or additive interactions with antibiotics, which suggests their potential for use in antibacterial therapy, reducing the toxicity of the antibiotics used and the risk of further development of bacterial resistance. Unfortunately, there are also compounds which interact antagonistically, potentially hindering the therapy of bacterial infection. Depending on its mechanism of action, each compound can behave differently in combination with different antibiotics and when acting against various bacterial strains.
Antibiotics are among the most often used medications in human healthcare and agriculture. Overusing these substances can lead to complications such as increasing antibiotic resistance in bacteria or a toxic effect when administering large amounts. To solve these problems, new solutions in antibacterial therapy are needed. The use of natural products in medicine has been known for centuries. Some of them have antibacterial activity, hence the idea to combine their activity with commercial antibiotics to reduce the latter's use. This review presents collected information on natural compounds (terpenes, alkaloids, flavonoids, tannins, sulfoxides, and mycotoxins), of which various drug interactions have been observed. Many of the indicated compounds show synergistic or additive interactions with antibiotics, which suggests their potential for use in antibacterial therapy, reducing the toxicity of the antibiotics used and the risk of further development of bacterial resistance. Unfortunately, there are also compounds which interact antagonistically, potentially hindering the therapy of bacterial infection. Depending on its mechanism of action, each compound can behave differently in combination with different antibiotics and when acting against various bacterial strains.
2024, 14(1): 39-51.
doi: 10.1016/j.jpha.2023.09.003
摘要：
Diabetic nephropathy (DN) is an enduring condition that leads to inflammation and affects a substantial number of individuals with diabetes worldwide. A gradual reduction in glomerular filtration and emergence of proteins in the urine are typical aspects of DN, ultimately resulting in renal failure. Mounting evidence suggests that immunological and inflammatory factors are crucial for the development of DN. Therefore, the activation of innate immunity by resident renal and immune cells is critical for initiating and perpetuating inflammation. Toll-like receptors (TLRs) are an important group of receptors that identify patterns and activate immune responses and inflammation. Meanwhile, inflammatory responses in the liver, pancreatic islets, and kidneys involve inflammasomes and chemokines that generate pro-inflammatory cytokines. Moreover, the activation of the complement cascade can be triggered by glycated proteins. This review highlights recent findings elucidating how the innate immune system contributes to tissue fibrosis and organ dysfunction, ultimately leading to renal failure. This review also discusses innovative approaches that can be utilized to modulate the innate immune responses in DN for therapeutic purposes.
Diabetic nephropathy (DN) is an enduring condition that leads to inflammation and affects a substantial number of individuals with diabetes worldwide. A gradual reduction in glomerular filtration and emergence of proteins in the urine are typical aspects of DN, ultimately resulting in renal failure. Mounting evidence suggests that immunological and inflammatory factors are crucial for the development of DN. Therefore, the activation of innate immunity by resident renal and immune cells is critical for initiating and perpetuating inflammation. Toll-like receptors (TLRs) are an important group of receptors that identify patterns and activate immune responses and inflammation. Meanwhile, inflammatory responses in the liver, pancreatic islets, and kidneys involve inflammasomes and chemokines that generate pro-inflammatory cytokines. Moreover, the activation of the complement cascade can be triggered by glycated proteins. This review highlights recent findings elucidating how the innate immune system contributes to tissue fibrosis and organ dysfunction, ultimately leading to renal failure. This review also discusses innovative approaches that can be utilized to modulate the innate immune responses in DN for therapeutic purposes.
2022, 12(1): 178-185.
doi: 10.1016/j.jpha.2021.07.005
摘要：
Diagnosing Alzheimer's disease (AD) in the early stage is challenging. Informative biomarkers can be of great value for population-based screening. Metabolomics studies have been used to find potential biomarkers, but commonly used tissue sources can be difficult to obtain. The objective of this study was to determine the potential utility of erythrocyte metabolite profiles in screening for AD. Unlike some commonly-used sources such as cerebrospinal fluid and brain tissue, erythrocytes are plentiful and easily accessed. Moreover, erythrocytes are metabolically active, a feature that distinguishes this sample source from other bodily fluids like plasma and urine. In this preliminary pilot study, the erythrocyte metabolomes of 10 histopathologically confirmed AD patients and 10 patients without AD (control (CTRL)) were compared. Whole blood was collected post-mortem and erythrocytes were analyzed using ultra-performance liquid chromatography tandem mass spectrometry. Over 750 metabolites were identified in AD and CTRL erythrocytes. Seven were increased in AD while 24 were decreased (P<0.05). The majority of the metabolites increased in AD were associated with amino acid metabolism and all of the decreased metabolites were associated with lipid metabolism. Prominent among the potential biomarkers were 10 sphingolipid or sphingolipid-related species that were consistently decreased in AD patients. Sphingolipids have been previously implicated in AD and other neurological conditions. Furthermore, previous studies have shown that erythrocyte sphingolipid concentrations vary widely in normal, healthy adults. Together, these observations suggest that certain erythrocyte lipid phenotypes could be markers of risk for development of AD.
Diagnosing Alzheimer's disease (AD) in the early stage is challenging. Informative biomarkers can be of great value for population-based screening. Metabolomics studies have been used to find potential biomarkers, but commonly used tissue sources can be difficult to obtain. The objective of this study was to determine the potential utility of erythrocyte metabolite profiles in screening for AD. Unlike some commonly-used sources such as cerebrospinal fluid and brain tissue, erythrocytes are plentiful and easily accessed. Moreover, erythrocytes are metabolically active, a feature that distinguishes this sample source from other bodily fluids like plasma and urine. In this preliminary pilot study, the erythrocyte metabolomes of 10 histopathologically confirmed AD patients and 10 patients without AD (control (CTRL)) were compared. Whole blood was collected post-mortem and erythrocytes were analyzed using ultra-performance liquid chromatography tandem mass spectrometry. Over 750 metabolites were identified in AD and CTRL erythrocytes. Seven were increased in AD while 24 were decreased (P<0.05). The majority of the metabolites increased in AD were associated with amino acid metabolism and all of the decreased metabolites were associated with lipid metabolism. Prominent among the potential biomarkers were 10 sphingolipid or sphingolipid-related species that were consistently decreased in AD patients. Sphingolipids have been previously implicated in AD and other neurological conditions. Furthermore, previous studies have shown that erythrocyte sphingolipid concentrations vary widely in normal, healthy adults. Together, these observations suggest that certain erythrocyte lipid phenotypes could be markers of risk for development of AD.
2022, 12(4): 664-682.
doi: 10.1016/j.jpha.2022.01.001
摘要：
XueBiJing is an intravenous five-herb injection used to treat sepsis in China. The study aimed to develop a liquid chromatography-tandem mass spectrometry (LC-MS/MS)- or liquid chromatography-ultraviolet (LC-UV)-based assay for quality evaluation of XueBiJing. Assay development involved identifying marker constituents to make the assay therapeutically relevant and building a reliable one-point calibrator for monitoring the various analytes in parallel. Nine marker constituents from the five herbs were selected based on XueBiJing's chemical composition, pharmacokinetics, and pharmacodynamics. A selectivity test (for "similarity of response") was developed to identify and minimize interference by non-target constituents. Then, an intercept test was developed to fulfill "linearity through zero" for each analyte (absolute ratio of intercept to C response, <2%). Using the newly developed assays, we analyzed samples from 33 batches of XueBiJing, manufactured over three years, and found small batch-to-batch variability in contents of the marker constituents (4.1%-14.8%), except for senkyunolide I (26.5%).
XueBiJing is an intravenous five-herb injection used to treat sepsis in China. The study aimed to develop a liquid chromatography-tandem mass spectrometry (LC-MS/MS)- or liquid chromatography-ultraviolet (LC-UV)-based assay for quality evaluation of XueBiJing. Assay development involved identifying marker constituents to make the assay therapeutically relevant and building a reliable one-point calibrator for monitoring the various analytes in parallel. Nine marker constituents from the five herbs were selected based on XueBiJing's chemical composition, pharmacokinetics, and pharmacodynamics. A selectivity test (for "similarity of response") was developed to identify and minimize interference by non-target constituents. Then, an intercept test was developed to fulfill "linearity through zero" for each analyte (absolute ratio of intercept to C response, <2%). Using the newly developed assays, we analyzed samples from 33 batches of XueBiJing, manufactured over three years, and found small batch-to-batch variability in contents of the marker constituents (4.1%-14.8%), except for senkyunolide I (26.5%).
2022, 12(5): 808-813.
doi: 10.1016/j.jpha.2022.05.009
摘要：
The identification of tumor-related microRNAs (miRNAs) exhibits excellent promise for the early diagnosis of cancer and other bioanalytical applications. Therefore, we developed a sensitive and efficient biosensor using polyadenine (polyA)-mediated fluorescent spherical nucleic acid (FSNA) for miRNA analysis based on strand displacement reactions on gold nanoparticle (AuNP) surfaces and electrokinetic signal amplification (ESA) on a microfluidic chip. In this FSNA, polyA-DNA biosensor was anchored on AuNP surfaces via intrinsic affinity between adenine and Au. The upright conformational polyA-DNA recognition block hybridized with 6-carboxyfluorescein-labeled reporter-DNA, resulting in fluorescence quenching of FSNA probes induced by AuNP-based resonance energy transfer. Reporter DNA was replaced in the presence of target miRNA, leading to the recovery of reporter-DNA fluorescence. Subsequently, reporter-DNAs were accumulated and detected in the front of with Nafion membrane in the microchannel by ESA. Our method showed high selectivity and sensitivity with a limit of detection of 1.3 pM. This method could also be used to detect miRNA-21 in human serum and urine samples, with recoveries of 104.0%–113.3% and 104.9%–108.0%, respectively. Furthermore, we constructed a chip with three parallel channels for the simultaneous detection of multiple tumor-related miRNAs (miRNA-21, miRNA-141, and miRNA-375), which increased the detection efficiency. Our universal method can be applied to other DNA/RNA analyses by altering recognition sequences.
The identification of tumor-related microRNAs (miRNAs) exhibits excellent promise for the early diagnosis of cancer and other bioanalytical applications. Therefore, we developed a sensitive and efficient biosensor using polyadenine (polyA)-mediated fluorescent spherical nucleic acid (FSNA) for miRNA analysis based on strand displacement reactions on gold nanoparticle (AuNP) surfaces and electrokinetic signal amplification (ESA) on a microfluidic chip. In this FSNA, polyA-DNA biosensor was anchored on AuNP surfaces via intrinsic affinity between adenine and Au. The upright conformational polyA-DNA recognition block hybridized with 6-carboxyfluorescein-labeled reporter-DNA, resulting in fluorescence quenching of FSNA probes induced by AuNP-based resonance energy transfer. Reporter DNA was replaced in the presence of target miRNA, leading to the recovery of reporter-DNA fluorescence. Subsequently, reporter-DNAs were accumulated and detected in the front of with Nafion membrane in the microchannel by ESA. Our method showed high selectivity and sensitivity with a limit of detection of 1.3 pM. This method could also be used to detect miRNA-21 in human serum and urine samples, with recoveries of 104.0%–113.3% and 104.9%–108.0%, respectively. Furthermore, we constructed a chip with three parallel channels for the simultaneous detection of multiple tumor-related miRNAs (miRNA-21, miRNA-141, and miRNA-375), which increased the detection efficiency. Our universal method can be applied to other DNA/RNA analyses by altering recognition sequences.
2023, 13(3): 315-322.
doi: 10.1016/j.jpha.2023.02.003
摘要：
Trace amines (TAs) are metabolically related to catecholamine and associated with cancer and neurological disorders. Comprehensive measurement of TAs is essential for understanding pathological processes and providing proper drug intervention. However, the trace amounts and chemical instability of TAs challenge quantification. Here, diisopropyl phosphite coupled with chip two-dimensional (2D) liquid chromatography tandem triple-quadrupole mass spectrometry (LC-QQQ/MS) was developed to simultaneously determine TAs and associated metabolites. The results showed that the sensitivities of TAs increased up to 5520 times compared with those using nonderivatized LC-QQQ/MS. This sensitive method was utilized to investigate their alterations in hepatoma cells after treatment with sorafenib. The significantly altered TAs and associated metabolites suggested that phenylalanine and tyrosine metabolic pathways were related to sorafenib treatment in Hep3B cells. This sensitive method has great potential to elucidate the mechanism and diagnose diseases considering that an increasing number of physiological functions of TAs have been discovered in recent decades.
Trace amines (TAs) are metabolically related to catecholamine and associated with cancer and neurological disorders. Comprehensive measurement of TAs is essential for understanding pathological processes and providing proper drug intervention. However, the trace amounts and chemical instability of TAs challenge quantification. Here, diisopropyl phosphite coupled with chip two-dimensional (2D) liquid chromatography tandem triple-quadrupole mass spectrometry (LC-QQQ/MS) was developed to simultaneously determine TAs and associated metabolites. The results showed that the sensitivities of TAs increased up to 5520 times compared with those using nonderivatized LC-QQQ/MS. This sensitive method was utilized to investigate their alterations in hepatoma cells after treatment with sorafenib. The significantly altered TAs and associated metabolites suggested that phenylalanine and tyrosine metabolic pathways were related to sorafenib treatment in Hep3B cells. This sensitive method has great potential to elucidate the mechanism and diagnose diseases considering that an increasing number of physiological functions of TAs have been discovered in recent decades.
2023, 13(3): 223-238.
doi: 10.1016/j.jpha.2023.02.005
摘要：
Ensuring food safety is paramount worldwide. Developing effective detection methods to ensure food safety can be challenging owing to trace hazards, long detection time, and resource-poor sites, in addition to the matrix effects of food. Personal glucose meter (PGM), a classic point-of-care testing device, possesses unique application advantages, demonstrating promise in food safety. Currently, many studies have used PGM-based biosensors and signal amplification technologies to achieve sensitive and specific detection of food hazards. Signal amplification technologies have the potential to greatly improve the analytical performance and integration of PGMs with biosensors, which is crucial for solving the challenges associated with the use of PGMs for food safety analysis. This review introduces the basic detection principle of a PGM-based sensing strategy, which consists of three key factors: target recognition, signal transduction, and signal output. Representative studies of existing PGM-based sensing strategies combined with various signal amplification technologies (nanomaterial-loaded multienzyme labeling, nucleic acid reaction, DNAzyme catalysis, responsive nanomaterial encapsulation, and others) in the field of food safety detection are reviewed. Future perspectives and potential opportunities and challenges associated with PGMs in the field of food safety are discussed. Despite the need for complex sample preparation and the lack of standardization in the field, using PGMs in combination with signal amplification technology shows promise as a rapid and cost-effective method for food safety hazard analysis.
Ensuring food safety is paramount worldwide. Developing effective detection methods to ensure food safety can be challenging owing to trace hazards, long detection time, and resource-poor sites, in addition to the matrix effects of food. Personal glucose meter (PGM), a classic point-of-care testing device, possesses unique application advantages, demonstrating promise in food safety. Currently, many studies have used PGM-based biosensors and signal amplification technologies to achieve sensitive and specific detection of food hazards. Signal amplification technologies have the potential to greatly improve the analytical performance and integration of PGMs with biosensors, which is crucial for solving the challenges associated with the use of PGMs for food safety analysis. This review introduces the basic detection principle of a PGM-based sensing strategy, which consists of three key factors: target recognition, signal transduction, and signal output. Representative studies of existing PGM-based sensing strategies combined with various signal amplification technologies (nanomaterial-loaded multienzyme labeling, nucleic acid reaction, DNAzyme catalysis, responsive nanomaterial encapsulation, and others) in the field of food safety detection are reviewed. Future perspectives and potential opportunities and challenges associated with PGMs in the field of food safety are discussed. Despite the need for complex sample preparation and the lack of standardization in the field, using PGMs in combination with signal amplification technology shows promise as a rapid and cost-effective method for food safety hazard analysis.
2023, 13(9): 1024-1040.
doi: 10.1016/j.jpha.2023.06.012
摘要：
Specnuezhenide (SNZ) is among the main components of Fructus Ligustri Lucidi, which has anti-inflammation, anti-oxidation, and anti-tumor effect. The low bioavailability makes it difficult to explain the mechanism of pharmacological effect of SNZ. In this study, the role of the gut microbiota in the metabolism and pharmacokinetics characteristics of SNZ as well as the pharmacological meaning were explored. SNZ can be rapidly metabolized by the gut microbiome, and two intestinal bacterial metabolites of SNZ, salidroside and tyrosol, were discovered. In addition, carboxylesterase may be the main intestinal bacterial enzyme that mediates its metabolism. At the same time, no metabolism was found in the incubation system of SNZ with liver microsomes or liver homogenate, indicating that the gut microbiota is the main part involved in the metabolism of SNZ. In addition, pharmacokinetic studies showed that salidroside and tyrosol can be detected in plasma in the presence of gut microbiota. Interestingly, tumor development was inhibited in a colorectal tumor mice model administered orally with SNZ, which indicated that SNZ exhibited potential to inhibit tumor growth, and tissue distribution studies showed that salidroside and tyrosol could be distributed in tumor tissues. At the same time, SNZ modulated the structure of gut microbiota and fungal group, which may be the mechanism governing the antitumoral activity of SNZ. Furthermore, SNZ stimulates the secretion of short-chain fatty acids by intestinal flora in vitro and in vivo. In the future, targeting gut microbes and the interaction between natural products and gut microbes could lead to the discovery and development of new drugs.
Specnuezhenide (SNZ) is among the main components of Fructus Ligustri Lucidi, which has anti-inflammation, anti-oxidation, and anti-tumor effect. The low bioavailability makes it difficult to explain the mechanism of pharmacological effect of SNZ. In this study, the role of the gut microbiota in the metabolism and pharmacokinetics characteristics of SNZ as well as the pharmacological meaning were explored. SNZ can be rapidly metabolized by the gut microbiome, and two intestinal bacterial metabolites of SNZ, salidroside and tyrosol, were discovered. In addition, carboxylesterase may be the main intestinal bacterial enzyme that mediates its metabolism. At the same time, no metabolism was found in the incubation system of SNZ with liver microsomes or liver homogenate, indicating that the gut microbiota is the main part involved in the metabolism of SNZ. In addition, pharmacokinetic studies showed that salidroside and tyrosol can be detected in plasma in the presence of gut microbiota. Interestingly, tumor development was inhibited in a colorectal tumor mice model administered orally with SNZ, which indicated that SNZ exhibited potential to inhibit tumor growth, and tissue distribution studies showed that salidroside and tyrosol could be distributed in tumor tissues. At the same time, SNZ modulated the structure of gut microbiota and fungal group, which may be the mechanism governing the antitumoral activity of SNZ. Furthermore, SNZ stimulates the secretion of short-chain fatty acids by intestinal flora in vitro and in vivo. In the future, targeting gut microbes and the interaction between natural products and gut microbes could lead to the discovery and development of new drugs.
2023, 13(9): 1041-1057.
doi: 10.1016/j.jpha.2023.04.018
摘要：
Herbal medicines are popular natural medicines that have been used for decades. The use of alternative medicines continues to expand rapidly across the world. The World Health Organization suggests that quality assessment of natural medicines is essential for any therapeutic or health care applications, as their therapeutic potential varies between different geographic origins, plant species, and varieties. Classification of herbal medicines based on a limited number of secondary metabolites is not an ideal approach. Their quality should be considered based on a complete metabolic profile, as their pharmacological activity is not due to a few specific secondary metabolites but rather a larger group of bioactive compounds. A holistic and integrative approach using rapid and nondestructive analytical strategies for the screening of herbal medicines is required for robust characterization. In this study, a rapid and effective quality assessment system for geographical traceability, species, and variety-specific authenticity of the widely used natural medicines turmeric, Ocimum, and Withania somnifera was investigated using Fourier transform near-infrared (FT-NIR) spectroscopy-based metabolic fingerprinting. Four different geographical origins of turmeric, five different Ocimum species, and three different varieties of roots and leaves of Withania somnifera were studied with the aid of machine learning approaches. Extremely good discrimination (R2 > 0.98, Q2 > 0.97, and accuracy = 1.0) with sensitivity and specificity of 100% was achieved using this metabolic fingerprinting strategy. Our study demonstrated that FT-NIR-based rapid metabolic fingerprinting can be used as a robust analytical method to authenticate several important medicinal herbs.
Herbal medicines are popular natural medicines that have been used for decades. The use of alternative medicines continues to expand rapidly across the world. The World Health Organization suggests that quality assessment of natural medicines is essential for any therapeutic or health care applications, as their therapeutic potential varies between different geographic origins, plant species, and varieties. Classification of herbal medicines based on a limited number of secondary metabolites is not an ideal approach. Their quality should be considered based on a complete metabolic profile, as their pharmacological activity is not due to a few specific secondary metabolites but rather a larger group of bioactive compounds. A holistic and integrative approach using rapid and nondestructive analytical strategies for the screening of herbal medicines is required for robust characterization. In this study, a rapid and effective quality assessment system for geographical traceability, species, and variety-specific authenticity of the widely used natural medicines turmeric, Ocimum, and Withania somnifera was investigated using Fourier transform near-infrared (FT-NIR) spectroscopy-based metabolic fingerprinting. Four different geographical origins of turmeric, five different Ocimum species, and three different varieties of roots and leaves of Withania somnifera were studied with the aid of machine learning approaches. Extremely good discrimination (R2 > 0.98, Q2 > 0.97, and accuracy = 1.0) with sensitivity and specificity of 100% was achieved using this metabolic fingerprinting strategy. Our study demonstrated that FT-NIR-based rapid metabolic fingerprinting can be used as a robust analytical method to authenticate several important medicinal herbs.
2023, 13(11): 1353-1364.
doi: 10.1016/j.jpha.2023.06.009
摘要：
Amino-containing compounds, including amino acids, aliphatic amines, aromatic amines, small peptides and catecholamines, are involved in various biological processes and play vital roles in multiple metabolic pathways. Previous studies indicated that some amino-containing metabolites are significant diagnostic and prognostic biomarkers of gastric cancer. However, the discovery of precise biomarkers for the preoperative diagnosis of gastric cancer is still in an urgent need. Herein, we established a polarity-regulated derivatization method coupled with liquid chromatography-mass spectrometry (LC-MS) for amino-containing metabolites profiling in the serum samples of patients with gastric cancer and healthy controls, based on our newly designed and synthesized derivatization reagent (S)-3-(1-(diisopropoxyphosphoryl) pyrrolidine-2-carboxamido)-N-hydroxysuccinimidyl ester (3-DP-NHS). Enhanced separation efficiency and detection sensitivity for amino-containing metabolites were achieved after derivatization. This method exhibited good linearity, recovery, intra- and inter-day precision and accuracy. Only 5 μL serum is needed for untargeted analysis, enabling 202 amino-containing metabolites to be detected. Statistical analysis revealed altered amino acid metabolisms in patients with gastric cancer. Furthermore, ultra high performance liquid chromatography coupled with mass spectrometry (UHPLC-MS/MS) analysis quantification revealed increased serum levels of tryptamine and decreased concentrations of arginine and tryptophan in patients with gastric cancer. Receiver operating characteristic (ROC) curves indicated that an increased tryptamine/tryptophan ratio could serve as a potential biomarker for gastric cancer diagnosis. This study demostrated the possibility of using serum amino acid biomarkers for gastric cancer diagnosis, providing new avenues for the treatment of gastric cancer.
Amino-containing compounds, including amino acids, aliphatic amines, aromatic amines, small peptides and catecholamines, are involved in various biological processes and play vital roles in multiple metabolic pathways. Previous studies indicated that some amino-containing metabolites are significant diagnostic and prognostic biomarkers of gastric cancer. However, the discovery of precise biomarkers for the preoperative diagnosis of gastric cancer is still in an urgent need. Herein, we established a polarity-regulated derivatization method coupled with liquid chromatography-mass spectrometry (LC-MS) for amino-containing metabolites profiling in the serum samples of patients with gastric cancer and healthy controls, based on our newly designed and synthesized derivatization reagent (S)-3-(1-(diisopropoxyphosphoryl) pyrrolidine-2-carboxamido)-N-hydroxysuccinimidyl ester (3-DP-NHS). Enhanced separation efficiency and detection sensitivity for amino-containing metabolites were achieved after derivatization. This method exhibited good linearity, recovery, intra- and inter-day precision and accuracy. Only 5 μL serum is needed for untargeted analysis, enabling 202 amino-containing metabolites to be detected. Statistical analysis revealed altered amino acid metabolisms in patients with gastric cancer. Furthermore, ultra high performance liquid chromatography coupled with mass spectrometry (UHPLC-MS/MS) analysis quantification revealed increased serum levels of tryptamine and decreased concentrations of arginine and tryptophan in patients with gastric cancer. Receiver operating characteristic (ROC) curves indicated that an increased tryptamine/tryptophan ratio could serve as a potential biomarker for gastric cancer diagnosis. This study demostrated the possibility of using serum amino acid biomarkers for gastric cancer diagnosis, providing new avenues for the treatment of gastric cancer.
2022, 12(1): 87-95.
doi: 10.1016/j.jpha.2021.03.002
摘要：
Natural long-chain alkanol and alkyl carboxylic acid were used to prepare novel hydrophobic deep eutectic solvents (HDESs). These HDESs are liquid at room temperature and have low viscosity (<12.26 mPa‧s), low polarity (lower than that of methanol, ChCl-based deep eutectic solvents and other reported HDESs), and low density (<0.928 g/mL). A simple one-pot method based on a novel HDES–water two-phase extraction system was constructed for the extraction of weak-polarity bioactive components, anthraquinones, from Rhei Radix et Rhizoma. This HDES-based new extraction method does not consume hazardous organic solvents and can obtain a total anthraquinone yield of 21.52 mg/g, which is close to that obtained by the Chinese pharmacopoeia method (21.22 mg/g) and considerably higher than those by other reported HDESs-based extraction methods (14.20–20.09 mg/g, p < 0.01). The high extraction yield can be mainly attributed to the severe destruction of the RRR cell walls by the extraction system and the excellent dissolving ability of novel HDESs for anthraquinones.
Natural long-chain alkanol and alkyl carboxylic acid were used to prepare novel hydrophobic deep eutectic solvents (HDESs). These HDESs are liquid at room temperature and have low viscosity (<12.26 mPa‧s), low polarity (lower than that of methanol, ChCl-based deep eutectic solvents and other reported HDESs), and low density (<0.928 g/mL). A simple one-pot method based on a novel HDES–water two-phase extraction system was constructed for the extraction of weak-polarity bioactive components, anthraquinones, from Rhei Radix et Rhizoma. This HDES-based new extraction method does not consume hazardous organic solvents and can obtain a total anthraquinone yield of 21.52 mg/g, which is close to that obtained by the Chinese pharmacopoeia method (21.22 mg/g) and considerably higher than those by other reported HDESs-based extraction methods (14.20–20.09 mg/g, p < 0.01). The high extraction yield can be mainly attributed to the severe destruction of the RRR cell walls by the extraction system and the excellent dissolving ability of novel HDESs for anthraquinones.
2022, 12(2): 215-220.
doi: 10.1016/j.jpha.2021.12.003
摘要：
As of August 16, 2021, there have been 207,173,086 confirmed cases and 4,361,996 deaths due to the coronavirus disease (COVID-19), and the pandemic remains a global challenge. To date, no effective and approved drugs are available for the treatment of COVID-19. Angiotensin-converting enzyme 2 (ACE2) plays a crucial role in the invasion into host cells by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the etiological agent of COVID-19. Notably, ACE2 density is influenced by medical conditions, such as hypertension, or by drugs, including angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs), which can change the fate of SARS-CoV-2 infectivity. ACE2 is a target for these drugs and can be manipulated to limit the viral entry and replication within the cells. Different strategies aimed at blocking ACE2 with small molecules, peptides, and antibodies, or by neutralizing the virus through its competitive binding with human recombinant soluble ACE2 (hrsACE2) are currently under investigation. In this article, we review the current state of knowledge that emphasizes the need to find effective therapeutic agents against COVID-19 by exploiting ACE2 as a potential target. The increased soluble ACE2 levels and the application of hrsACE2 in patients with COVID-19 can be implemented to control the disease. It has not yet been established whether hypertension and other comorbidities, independent of age, have a direct role in COVID-19. Therefore, the use of renin-angiotensin system inhibitors, ACEIs and ARBs, should not be discontinued during COVID-19 treatment.
As of August 16, 2021, there have been 207,173,086 confirmed cases and 4,361,996 deaths due to the coronavirus disease (COVID-19), and the pandemic remains a global challenge. To date, no effective and approved drugs are available for the treatment of COVID-19. Angiotensin-converting enzyme 2 (ACE2) plays a crucial role in the invasion into host cells by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the etiological agent of COVID-19. Notably, ACE2 density is influenced by medical conditions, such as hypertension, or by drugs, including angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs), which can change the fate of SARS-CoV-2 infectivity. ACE2 is a target for these drugs and can be manipulated to limit the viral entry and replication within the cells. Different strategies aimed at blocking ACE2 with small molecules, peptides, and antibodies, or by neutralizing the virus through its competitive binding with human recombinant soluble ACE2 (hrsACE2) are currently under investigation. In this article, we review the current state of knowledge that emphasizes the need to find effective therapeutic agents against COVID-19 by exploiting ACE2 as a potential target. The increased soluble ACE2 levels and the application of hrsACE2 in patients with COVID-19 can be implemented to control the disease. It has not yet been established whether hypertension and other comorbidities, independent of age, have a direct role in COVID-19. Therefore, the use of renin-angiotensin system inhibitors, ACEIs and ARBs, should not be discontinued during COVID-19 treatment.
2022, 12(2): 350-354.
doi: 10.1016/j.jpha.2021.04.002
摘要：
Blighia sapida (B. sapida) K.D. Koenig (Family Sapindaceae) is a branchless straight bole approximately 15 m in length. The study evaluated the antioxidant and anti-inflammatory activities of ethanol extract and fractions of B. sapida stem-bark using in vitro methods. Ethanol extract and its fractions were investigated for 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging activity, ferric reducing antioxidant power (FRAP), total antioxidant capacity (TAC), and quantitative phenolic and flavonoid contents. Anti-inflammatory activity was evaluated using albumin denaturation and membrane stabilization assays. The extract and its fractions exhibited radical scavenging and anti-inflammatory properties. The ethyl acetate fraction possessed maximum phenolic and flavonoid contents (136.67 ±1.55 gallic acid equivalent mg/g and 75.76 ±4.03 quercetin equivalent mg/g, respectively). Antioxidant studies revealed that the ethyl acetate fraction displayed superior activity with an IC50 = 0.09 ±0.03 mg/mL DPPH, and values of 146.96 ±3.81 ascorbic acid equivalent (AAE) mg/g and 359.20 ±4.98 AAE mg/g for FRAP and TAC, respectively. Furthermore, the anti-inflammatory activity was revealed by inhibition of heat-induced albumin denaturation and red blood cell membrane stabilization at concentrations of 200–1000 μg/mL and 50–250 μg/mL, respectively. The ethanol extract and fractions exhibited antioxidant and anti-inflammatory activities, with ethyl acetate fraction showing superior activity, which could be attributed to secondary metabolites, mainly phenolic compounds. Overall, the antioxidant and anti-inflammatory activities of B. sapida can be exploited by ethnomedicinal users.
Blighia sapida (B. sapida) K.D. Koenig (Family Sapindaceae) is a branchless straight bole approximately 15 m in length. The study evaluated the antioxidant and anti-inflammatory activities of ethanol extract and fractions of B. sapida stem-bark using in vitro methods. Ethanol extract and its fractions were investigated for 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging activity, ferric reducing antioxidant power (FRAP), total antioxidant capacity (TAC), and quantitative phenolic and flavonoid contents. Anti-inflammatory activity was evaluated using albumin denaturation and membrane stabilization assays. The extract and its fractions exhibited radical scavenging and anti-inflammatory properties. The ethyl acetate fraction possessed maximum phenolic and flavonoid contents (136.67 ±1.55 gallic acid equivalent mg/g and 75.76 ±4.03 quercetin equivalent mg/g, respectively). Antioxidant studies revealed that the ethyl acetate fraction displayed superior activity with an IC50 = 0.09 ±0.03 mg/mL DPPH, and values of 146.96 ±3.81 ascorbic acid equivalent (AAE) mg/g and 359.20 ±4.98 AAE mg/g for FRAP and TAC, respectively. Furthermore, the anti-inflammatory activity was revealed by inhibition of heat-induced albumin denaturation and red blood cell membrane stabilization at concentrations of 200–1000 μg/mL and 50–250 μg/mL, respectively. The ethanol extract and fractions exhibited antioxidant and anti-inflammatory activities, with ethyl acetate fraction showing superior activity, which could be attributed to secondary metabolites, mainly phenolic compounds. Overall, the antioxidant and anti-inflammatory activities of B. sapida can be exploited by ethnomedicinal users.
2022, 12(6): 929-936.
doi: 10.1016/j.jpha.2022.06.003
摘要：
Therapeutic drug monitoring (TDM) has played an important role in clinical medicine for precise dosing. Currently, chromatographic technology and immunoassay detection are widely used in TDM and have met most of the needs of clinical drug therapy. However, some problems still exist in practical applications, such as complicated operation and the influence of endogenous substances. Surface plasmon resonance (SPR) has been applied to detect the concentrations of small molecules, including pesticide residues in crops and antibiotics in milk, which indicates its potential for in vivo drug detection. In this study, a new SPR-based biosensor for detecting chloramphenicol (CAP) in blood samples was developed and validated using methodological verification, including precision, accuracy, matrix effect, and extraction recovery rate, and compared with the classic ultra-performance liquid chromatography-ultraviolet (UPLC-UV) method. The detection range of SPR was 0.1–50 ng/mL and the limit of detection was 0.099 ± 0.023 ng/mL, which was lower than that of UPLC-UV. The intra-day and inter-day accuracies of SPR were 98%–114% and 110%–122%, which met the analysis requirement. The results show that the SPR biosensor is identical to UPLC-UV in the detection of CAP in rat blood samples; moreover, the SPR biosensor has better sensitivity. Therefore, the present study shows that SPR technology can be used for the detection of small molecules in the blood samples and has the potential to become a method for therapeutic drug monitoring.
Therapeutic drug monitoring (TDM) has played an important role in clinical medicine for precise dosing. Currently, chromatographic technology and immunoassay detection are widely used in TDM and have met most of the needs of clinical drug therapy. However, some problems still exist in practical applications, such as complicated operation and the influence of endogenous substances. Surface plasmon resonance (SPR) has been applied to detect the concentrations of small molecules, including pesticide residues in crops and antibiotics in milk, which indicates its potential for in vivo drug detection. In this study, a new SPR-based biosensor for detecting chloramphenicol (CAP) in blood samples was developed and validated using methodological verification, including precision, accuracy, matrix effect, and extraction recovery rate, and compared with the classic ultra-performance liquid chromatography-ultraviolet (UPLC-UV) method. The detection range of SPR was 0.1–50 ng/mL and the limit of detection was 0.099 ± 0.023 ng/mL, which was lower than that of UPLC-UV. The intra-day and inter-day accuracies of SPR were 98%–114% and 110%–122%, which met the analysis requirement. The results show that the SPR biosensor is identical to UPLC-UV in the detection of CAP in rat blood samples; moreover, the SPR biosensor has better sensitivity. Therefore, the present study shows that SPR technology can be used for the detection of small molecules in the blood samples and has the potential to become a method for therapeutic drug monitoring.
2023, 13(2): 201-208.
doi: 10.1016/j.jpha.2022.11.004
摘要：
Polysaccharides exhibit multiple pharmacological activities which are closely related to their structural features. Therefore, quantitatively quality control of polysaccharides based on their chemical characteristics is important for their application in biomedical and functional food sciences. However, polysaccharides are mixed macromolecular compounds that are difficult to isolate and lack standards, making them challenging to quantify directly. In this study, we proposed an improved saccharide mapping method based on the release of specific oligosaccharides for the assessment of Hericium erinaceus polysaccharides from laboratory cultured and different regions of China. Briefly, a polysaccharide from H. erinaceus was digested by β-(1-3)-glucanase, and the released specific oligosaccharides were labeled with 8-aminopyrene-1,3,6-trisulfonic-acid (APTS) and separated by using micellar electrokinetic chromatography (MEKC) coupled with laser induced fluorescence (LIF), and quantitatively estimated. MEKC presented higher resolution compared to polysaccharide analysis using carbohydrate gel electrophoresis (PACE), and provided great peak capacity between oligosaccharides with polymerization degree of 2 (DP2) and polymerization degree of 6 (DP6) in a dextran ladder separation. The results of high performance size exclusion chromatography coupled with multi-angle laser light scattering and refractive index detector (HPSEC-MALLS-RI) showed that 12 h was sufficient for complete digestion of polysaccharides from H. erinaceus. Laminaritriose (DP3) was used as an internal standard for quantification of all the oligosaccharides. The calibration curve for DP3 showed a good linear regression (R2 > 0.9988). The limit of detection (LOD) and limit of quantification (LOQ) values were 0.05 μg/mL and 0.2 μg/mL, respectively. The recovery for DP3 was 87.32 (±0.03)% in the three independent injections. To sum up, this proposed method is helpful for improving the quality control of polysaccharides from H. erinaceus as well as other materials.
Polysaccharides exhibit multiple pharmacological activities which are closely related to their structural features. Therefore, quantitatively quality control of polysaccharides based on their chemical characteristics is important for their application in biomedical and functional food sciences. However, polysaccharides are mixed macromolecular compounds that are difficult to isolate and lack standards, making them challenging to quantify directly. In this study, we proposed an improved saccharide mapping method based on the release of specific oligosaccharides for the assessment of Hericium erinaceus polysaccharides from laboratory cultured and different regions of China. Briefly, a polysaccharide from H. erinaceus was digested by β-(1-3)-glucanase, and the released specific oligosaccharides were labeled with 8-aminopyrene-1,3,6-trisulfonic-acid (APTS) and separated by using micellar electrokinetic chromatography (MEKC) coupled with laser induced fluorescence (LIF), and quantitatively estimated. MEKC presented higher resolution compared to polysaccharide analysis using carbohydrate gel electrophoresis (PACE), and provided great peak capacity between oligosaccharides with polymerization degree of 2 (DP2) and polymerization degree of 6 (DP6) in a dextran ladder separation. The results of high performance size exclusion chromatography coupled with multi-angle laser light scattering and refractive index detector (HPSEC-MALLS-RI) showed that 12 h was sufficient for complete digestion of polysaccharides from H. erinaceus. Laminaritriose (DP3) was used as an internal standard for quantification of all the oligosaccharides. The calibration curve for DP3 showed a good linear regression (R2 > 0.9988). The limit of detection (LOD) and limit of quantification (LOQ) values were 0.05 μg/mL and 0.2 μg/mL, respectively. The recovery for DP3 was 87.32 (±0.03)% in the three independent injections. To sum up, this proposed method is helpful for improving the quality control of polysaccharides from H. erinaceus as well as other materials.
2023, 13(8): 862-879.
doi: 10.1016/j.jpha.2023.02.007
摘要：
The role of glial scar after intracerebral hemorrhage (ICH) remains unclear. This study aimed to investigate whether microglia-astrocyte interaction affects glial scar formation and explore the specific function of glial scar. We used a pharmacologic approach to induce microglial depletion during different ICH stages and examine how ablating microglia affects astrocytic scar formation. Spatial transcriptomics (ST) analysis was performed to explore the potential ligand-receptor pair in the modulation of microglia-astrocyte interaction and to verify the functional changes of astrocytic scars at different periods. During the early stage, sustained microglial depletion induced disorganized astrocytic scar, enhanced neutrophil infiltration, and impaired tissue repair. ST analysis indicated that microglia-derived insulin like growth factor 1 (IGF1) modulated astrocytic scar formation via mechanistic target of rapamycin (mTOR) signaling activation. Moreover, repopulating microglia (RM) more strongly activated mTOR signaling, facilitating a more protective scar formation. The combination of IGF1 and osteopontin (OPN) was necessary and sufficient for RM function, rather than IGF1 or OPN alone. At the chronic stage of ICH, the overall net effect of astrocytic scar changed from protective to destructive and delayed microglial depletion could partly reverse this. The vital insight gleaned from our data is that sustained microglial depletion may not be a reasonable treatment strategy for early-stage ICH. Inversely, early-stage IGF1/OPN treatment combined with late-stage PLX3397 treatment is a promising therapeutic strategy. This prompts us to consider the complex temporal dynamics and overall net effect of microglia and astrocytes, and develop elaborate treatment strategies at precise time points after ICH.
The role of glial scar after intracerebral hemorrhage (ICH) remains unclear. This study aimed to investigate whether microglia-astrocyte interaction affects glial scar formation and explore the specific function of glial scar. We used a pharmacologic approach to induce microglial depletion during different ICH stages and examine how ablating microglia affects astrocytic scar formation. Spatial transcriptomics (ST) analysis was performed to explore the potential ligand-receptor pair in the modulation of microglia-astrocyte interaction and to verify the functional changes of astrocytic scars at different periods. During the early stage, sustained microglial depletion induced disorganized astrocytic scar, enhanced neutrophil infiltration, and impaired tissue repair. ST analysis indicated that microglia-derived insulin like growth factor 1 (IGF1) modulated astrocytic scar formation via mechanistic target of rapamycin (mTOR) signaling activation. Moreover, repopulating microglia (RM) more strongly activated mTOR signaling, facilitating a more protective scar formation. The combination of IGF1 and osteopontin (OPN) was necessary and sufficient for RM function, rather than IGF1 or OPN alone. At the chronic stage of ICH, the overall net effect of astrocytic scar changed from protective to destructive and delayed microglial depletion could partly reverse this. The vital insight gleaned from our data is that sustained microglial depletion may not be a reasonable treatment strategy for early-stage ICH. Inversely, early-stage IGF1/OPN treatment combined with late-stage PLX3397 treatment is a promising therapeutic strategy. This prompts us to consider the complex temporal dynamics and overall net effect of microglia and astrocytes, and develop elaborate treatment strategies at precise time points after ICH.
2023, 13(2): 142-155.
doi: 10.1016/j.jpha.2022.11.011
Abstract:
Celastrol targeting Nedd4 reduces Nrf2-mediated oxidative stress in astrocytes after ischemic stroke
2023, 13(2): 156-169.
doi: 10.1016/j.jpha.2022.12.002
Abstract:
2023, 13(2): 111-126.
doi: 10.1016/j.jpha.2022.12.004
Abstract:
2017, 7(4): 214-222.
Abstract:
2023, 13(7): 689-690.
doi: 10.1016/j.jpha.2023.07.005
Abstract:
2017, 7(4): 208-213.
Abstract:
2023, 13(2): ii-ii.
doi: 10.1016/S2095-1779(23)00009-6
Abstract:
2023, 13(2): 127-141.
doi: 10.1016/j.jpha.2022.11.009
Abstract:
